Clinical significance of signet ring cells in surgical esophageal and esophagogastric junction adenocarcinoma:A systematic review and meta-analysis

BACKGROUND The clinical significance of signet ring cells(SRCs)in surgical esophageal and esophagogastric junction adenocarcinoma(EEGJA)remains unclear now.AIM To explore the association between the presence of SRCs and the clinicopathological and prognostic characteristics in surgical EEGJA patients by combining and analyzing relevant studies.METHODS The PubMed,Web of Science,and EMBASE electronic databases were searched for the relevant literature up to March 28,2021.The relative risk(RR)with 95%confidence interval(CI)was calculated to assess the relationship between SRCs and clinicopathological parameters of surgical EEGJA patients,and the hazard ratio(HR)with 95%CI was calculated to explore the impact of SRC on the prognosis.All statistical analyses were conducted with STATA 12.0 software.RESULTS A total of ten articles were included,involving 30322 EEGJA patients.The pooled results indicated that the presence of SRCs was significantly associated with tumor location(RR:0.76,95%CI:0.61-0.96,P=0.022;I2=49.4%,P=0.160)and tumor-node-metastasis stage(RR:1.30,95%CI:1.02-1.65,P=0.031;I2=73.1%,P=0.002).Meanwhile,the presence of SRCs in surgical EEGJA patients predicted a poor overall survival(HR:1.36,95%CI:1.12-1.65,P=0.002;I2=85.7%,P<0.001)and disease-specific survival(HR:1.86,95%CI:1.55-2.25,P<0.001;I2=63.1%,P=0.043).CONCLUSION The presence of SRCs is related with advanced tumor stage and poor prognosis and could serve as a reliable and effective parameter for the prediction of postoperative survival and formulation of therapy strategy in EEGJA patients.However,more high-quality studies are still needed to verify the above findings.

Comparison of survival outcomes between transthoracic and transabdominal surgical approaches in patients with Siewert-Ⅱ/Ⅲesophagogastric junction adenocarcinoma:a single-institution retrospective cohort study

Objective： To compare the survival outcomes of transabdominal （TA） and transthoracic （TT） surgical approaches in patients with Siewert-II/III esophagogastric junction adenocarcinoma. Methods： This retrospective study was conducted in patients with Siewert-II/III esophagogastric junction adenocarcinoma who underwent either TT or TA operations in the West China Hospital between January 2006 and December 2009. Results： A total of 308 patients （109 in the TT and 199 in the TA groups） were included in this study with a follow-up rate of 87.3%. The median （P25, P75） number of harvested perigastric lymph nodes was 8 （5, 10） in the TT group and 23 （16, 34） in the TA group （P〈0.001）, and the number of positive perigastric lymph nodes was 2 （0, 5） in the TT group and 3 （1, 8） in the TA group （P〈0.004）. The 5-year overall survival （OS） rate was 36% in the TT group and 51% in the TA group （P=0.005）. Subgroup analysis by Siewert classification showed that 5-year OS rates for patients with Siewert II tumors were 38% and 48% in TT and TA groups, respectively （P=0.134）, whereas the 5-year OS rate for patients with Siewert III tumors was significantly lower in the TT group than that in the TA group （33% vs. 53%; P=0.010）. Multivariate analysis indicated that N2 and N3 stages, RI/R2 resection and a TT surgical approach were prognostic factors for poor OS. Conclusions： Improved perigastric lymph node dissection may be the main reason for better survival outcomes observed with a TA gastrectomy approach than with TT gastrectomy for Siewert III tumor patients.

Exploration and optimization of surgical techniques for laparoscopic transhiatal lower mediastinal lymph node dissection for adenocarcinoma of esophagogastric junction: A prospective IDEAL 2a study with qualitative design

Objective: To explore the change and feasibility of surgical techniques of laparoscopic transhiatal(TH)-lower mediastinal lymph node dissection(LMLND) for adenocarcinoma of the esophagogastric junction(AEG)according to Idea, Development, Exploration, Assessment, and Long-term follow-up(IDEAL) 2a standards.Methods: Patients diagnosed with AEG who underwent laparoscopic TH-LMLND were prospectively included from April 14, 2020, to March 26, 2021. Clinical and pathological information as well as surgical outcomes were quantitatively analyzed. Semistructured interviews with the surgeon after each operation were qualitatively analyzed.Results: Thirty-five patients were included. There were no cases of transition to open surgery, but three cases involved combination with transthoracic surgery. In qualitative analysis, 108 items under three main themes were detected: explosion, dissection, and reconstruction. Revised instruction was subsequently designed according to the change in surgical technique and the cognitive process behind it. Three patients had anastomotic leaks postoperatively, with one classified as Clavien-Dindo Ⅲa.Conclusions: The surgical technique of laparoscopic TH-LMLND is stable and feasible;further IDEAL 2b research is warranted.

Recent updates of therapeutic strategy of esophagogastric junction adenocarcinoma

The incidence of esophagogastric junction(EGJ)adenocarcinoma has been increasing in Asian countries.Despite the recent advances in multidisciplinary treatments,EGJ adenocarcinoma remains aggressive with unfavorable outcomes.Regarding surgical strategy,EGJ adenocarcinoma arises between the esophagus and the stomach,and thus tumor cells spread through the lymphatic system both upward to the mediastinum and downward to the abdomen.Nevertheless,an optimal extent of lymphadenectomy remains controversial.Regarding drug therapy,the latest topic in gastric and EGJ adenocarcinoma is trastuzumab deruxtecan,which is an antibody-drug conjugate consisting of an anti-HER2 antibody.In addition,many clinical trials have recently demonstrated the efficacy of immune checkpoint inhibitors.Meanwhile,recent advances in sequencing technology have revealed that gastroesophageal adenocarcinoma could be categorized into four molecular subtypes:epstein-Barr virus-associated,high-level microsatellite instability,genomically stable,and chromosomal instability tumors.Furthermore,these subtypes show distinct clinical phenotypes and molecular alterations.We review the current surgical strategy and drug treatment such as molecular-targeted agents,immune checkpoint inhibitors,and molecular-subtype-based therapeutic strategies in EGJ adenocarcinoma.Clinical and molecular characteristics and response to immune checkpoint inhibitors differ among molecular subtypes.Treatment strategies based on molecular subtypes may be clinically beneficial for patients with EGJ adenocarcinoma.

Lymph node metastasis and lymphadenectomy of resectable adenocarcinoma of the esophagogastric junction

Based on Siewert classification, adenocarcinomas of the esophagogastric junction （AEGs） have different behaviors of perigastric-mediastinal nodal metastasis. Siewert type I AEGs have higher incidence of mediastinal nodal metastasis than those of type H or III, especially at middle-upper mediastinum. With regard to the necessity of mediastinal lymphadenectomy, theoretically, transthoracic esophagogastrectomy with complete mediastinal lymphadenectomy is suggested for Siewert type I AEGs, while transhiatal total gastrectomy with lower mediastinal and D2 perigastric lymphadenectomy is a standard surgery for type II-III AEGs. Nevertheless, the mediastinal nodal metastasis is an independent factor of poor prognosis for any type of AEG.

Adenocarcinoma of esophagogastric junction:controversial classification,surgical management,and clinicopathology

In recent years the world is witnessing an increasing incidence of adenocarcinoma of esophagogastric junction （AEG）, which originates from epithelial tissue of esophagogastric junction （EGJ）, and mainly derives from Barrett＇s esophagus. It＇s now gaining more and more attention due to the controversial etiology, classification and treatment.

Optimal treatment for Siewert type Ⅱ and Ⅲ adenocarcinoma of the esophagogastric junction: A retrospective cohort study with long-term follow-up

AIM To determine the optimal treatment strategy for Siewert type Ⅱ and?Ⅲ?adenocarcinoma of the esophagogastric junction.METHODS We retrospectively reviewed the medical records of 83 patients with Siewert type?Ⅱ?and?Ⅲ?adenocarcinoma of the esophagogastric junction and calculated both an index of estimated benefit from lymph node dissection for each lymph node(LN) station and a lymph node ratio(LNR: ratio of number of positive lymph nodes to the total number of dissected lymph nodes). We used Cox proportional hazard models to clarify independent poor prognostic factors. The median duration of observation was 73 mo.RESULTS Indices of estimated benefit from LN dissection were as follows, in descending order: lymph nodes(LN) along the lesser curvature, 26.5; right paracardial LN, 22.8; left paracardial LN, 11.6; LN along the left gastric artery, 10.6. The 5-year overall survival(OS) rate was 58%. Cox regression analysis revealed that vigorous venous invasion(v2, v3)(HR = 5.99; 95%CI: 1.71-24.90) and LNR of > 0.16(HR = 4.29, 95%CI: 1.79-10.89) were independent poor prognostic factors for OS.CONCLUSION LN along the lesser curvature, right and left paracardial LN, and LN along the left gastric artery should be dissected in patients with Siewert type?Ⅱ?or?Ⅲ?adenoca rcinoma of the esophagogastric junction. Patients with vigorous venous invasion and LNR of > 0.16 should be treated with aggressive adjuvant chemotherapy to improve survival outcomes.

Adenocarcinoma of esophagogastric junction

To date,there has been a dramatic increase in the incidence of adenocarcinomas of the esophagogastric junction （AEG）worldwide.The classification of AEG,defined by Siewert and Stein,was approved at the second International Gastric Cancer Congress in Munich in April 1997.In accordance with the anatomic cardia,EGJC can be divided into three subtypes：type Ⅰ,adenocarcinoma of the distal esophagus with the center located within 1 cm above and 5 cm above the anatomic esophagogastric junction （EGJ）;type Ⅱ,true carcinoma of the cardia with the tumor center within 1 cm above and 2 cm below the EGJ;type Ⅲ,subcardial carcinoma with the tumor center between 2 and 5 cm below EGJ,which infiltrates the EGJ and distal esophagus from below （1）.

Recent advances in multidisciplinary therapy for adenocarcinoma of the esophagus and esophagogastric junction

Esophageal adenocarcinoma(EAC)and adenocarcinoma of the esophagogastric junction(EGJA)have long been associated with poor prognosis.With changes in the spectrum of the disease caused by economic development and demographic changes,the incidence of EAC and EGJA continues to increase,making them worthy of more attention from clinicians.For a long time,surgery has been the mainstay treatment for EAC and EGJA.With advanced techniques,endoscopic therapy,radiotherapy,chemotherapy,and other treatment methods have been developed,providing additional treatment options for patients with EAC and EGJA.In recent decades,the emergence of multidisciplinary therapy(MDT)has enabled the comprehensive treatment of tumors and made the treatment more flexible and diversified,which is conducive to achieving standardized and individualized treatment of EAC and EGJA to obtain a better prognosis.This review discusses recent advances in EAC and EGJA treatment in the surgicalcentered MDT mode in recent years.

Laparoscopic-assisted vs open transhiatal gastrectomy for Siewert type Ⅱ adenocarcinoma of the esophagogastric junction: A retrospective cohort study

BACKGROUND The studies of laparoscopic-assisted transhiatal gastrectomy(LTG) in patients with Siewert type Ⅱ adenocarcinoma of the esophagogastric junction(AEG) are scarce.AIM To compare the surgical efficiency of LTG with the open transhiatal gastrectomy(OTG) for patients with Siewert type Ⅱ AEG.METHODS We retrospectively evaluated a total of 578 patients with Siewert type Ⅱ AEG who have undergone LTG or OTG at the First Medical Center of the Chinese People’s Liberation Army General Hospital from January 2014 to December 2019. The short-term and long-term outcomes were compared between the LTG(n = 382) and OTG(n = 196) groups.RESULTS Compared with the OTG group, the LTG group had a longer operative time but less blood loss, shorter length of abdominal incision and an increased number of harvested lymph nodes(P < 0.05). Patients in the LTG group were able to eat liquid food, ambulate, expel flatus and discharge sooner than the OTG group(P < 0.05). No significant differences were found in postoperative complications and R0 resection. The 3-year overall survival and disease-free survival performed better in the LTG group compared with that in the OTG group(88.2% vs 79.2%, P = 0.011;79.7% vs 73.0%, P = 0.002, respectively). In the stratified analysis, both overall survival and disease-free survival were better in the LTG group than those in the OTG group for stage Ⅱ/Ⅲ patients(P < 0.05) but not for stage I patients.CONCLUSION For patients with Siewert type Ⅱ AEG, LTG is associated with better short-term outcomes and similar oncology safety. In addition, patients with advanced stage AEG may benefit more from LTG in the long-term outcomes.

Model established based on blood markers predicts overall survival in patients after radical resection of types Ⅱ and Ⅲ adenocarcinoma of the esophagogastric junction

BACKGROUND In recent years, the incidence of types Ⅱ and Ⅲ adenocarcinoma of the esophagogastric junction(AEG) has shown an obvious upward trend worldwide. The prognostic prediction after radical resection of AEG has not been well established.AIM To establish a prognostic model for AEG(types II and III) based on routine markers.METHODS A total of 355 patients who underwent curative AEG at The First Affiliated Hospital of Anhui Medical University from January 2014 to June 2015 were retrospectively included in this study. Univariate and multivariate analyses were performed to identify the independent risk factors. A nomogram was constructed based on Cox proportional hazards models. The new score models was analyzed by C index and calibration curves. The receiver operating characteristic(ROC) curve was used to compare the predictive accuracy of the scoring system and tumor-node-metastasis(TNM) stage. Overall survival was calculated using the Kaplan-Meier curve amongst different risk AEG patients.RESULTS Multivariate analysis showed that TNM stage(hazard ratio [HR] = 2.286, P = 0.008), neutrophil-tolymphocyte ratio(HR = 2.979, P = 0.001), and body mass index(HR = 0.626, P = 0.026) were independent prognostic factors. The new scoring system had a higher concordance index(0.697),and the calibration curves of the nomogram were reliable. The area under the ROC curve of the new score model(3-year: 0.725, 95% confidence interval [CI]: 0.676-0.777;5-year: 0.758, 95%CI:0.708-0.807) was larger than that of TNM staging(3-year: 0.630, 95%CI: 0.585-0.684;5-year: 0.665,95%CI: 0.616-0.715).CONCLUSION Based on the serum markers and other clinical indicators, we have developed a precise model to predict the prognosis of patients with AEG(types II and III). The new prognostic nomogram could effectively enhance the predictive value of the TNM staging system. This scoring system can be advantageous and helpful for surgeons and patients.

The unique phenotypes of adenocarcinoma of the esophagogastric junction in China

Adenocarcinoma of the esophagogastric junction （AEG） was proposed as a distinct disease for its rapidly increasing incidence. However, most studies of AEG were based primarily on the results of western patients and the studies on Chinese patients were deficient. Recently, some retrospective studies on AEG patients from our hospital show distinct clinical and pathological features compared with American patients （1-3）. In this editorial, we will focus on the unique phenotypes of Chinese AEG patients based on our studies and other reports.

A case of Photodynamic Therapy for Advanced Adenocarcinoma of Esophagogastric Junction

Photodynamic therapy(PDT)is a new minimally invasive technique for the treatment of tumors.Compared with traditional treatments such as surgery,radiotherapy and chemotherapy,PDT has the advantages of targeted killing of primary and recurrent tumor cells,less damage to surrounding normal tissue,less complications and high repetition rate.The purpose of this study was to investigate the short-term efficacy and adverse reactions of photodynamic therapy in advanced elderly patients with esophageal-gastric junction adenocarcinoma without surgical indications.A patient with advanced adenocarcinoma of esophagus and fundus was treated with photodynamic therapy under gastroscope.Intravenous drip of Cipofen(hematoporphyrin injection 150mg/0.9%saline 250ml)for 1 hour to keep the patient away from light.48 hours after administration,photodynamic therapy was performed with"Leimai"PDT630-A photodynamic therapy apparatus,3cm columnar optical fiber,laser treatment wavelength of 630nm,transmission efficiency of 0.70,output power of 1.4W,irradiation at the lower segment of the esophagus and cardia for 150s.The curative effect was evaluated by comparing gastroscopy before and after photodynamic therapy.Before treatment,there were proliferative lesions in the lower part of esophagus and cardia,erosion and necrosis on the surface,stricture of esophageal cavity,huge ulcer near gastric fundus,filthy moss and dam-like hyperplasia and eminence of surrounding mucosa.After treatment,the local mucosa at the entrance of cardia became white and there was no bleeding.Within four days after treatment,the symptoms of nausea and vomiting disappeared;the adverse reaction of retrosternal discomfort began to occur on the second day after operation,and the adverse reaction was not improved after photodynamic therapy.Photodynamic therapy has a significant short-term effect on advanced elderly patients with adenocarcinoma of the esophagogastric junction,which can significantly alleviate the clinical symptoms and relieve the pain of the patients.However,the adverse reactions can not be ignored.Therefore,photodynamic targeting therapy for tumor needs to be futher studied.It is believed that with the continuous development of high-performance photosensitizers and new generation lasers,and the continuous progress of endoscopy and image guidance technology,photodynamic therapy will become an important adjuvant or palliative treatment for tumor prevention and treatment.

Risk factors associated with early recurrence of adenocarcinoma of gastroesophageal junction after curative resection

Objective： To clarify the important clinicopathological factors affecting the early recurrence of adenocarcinoma of esophagogastric junction （/kEG）. Methods： We retrospectively reviewed the clinical data of 147 AEG patients who underwent R0 resection during the period from December 1995 to December 2007. Risk factors asssociated with the early recurrence were analyzed by X2 test and logistic regression test. Results： The mean time to tumor recurrence was 16.3 months after R0 resection, and the 1-year recurrence rate was 48.3%. Univariate analysis showed that the histological grade （poorly and moderately differentiated）, number of positive lymph nodes, and vascular invasion were significantly related with the early recurrence （P〈0.05）. Logistic multivariate regression analysis showed that only histological grade and vascular invasion were independently related with early tumor recurrence （P〈0.05）, Conclusions： Histological grade and vascular tumor recurrence after R0 resection for/kEG. invasion are independent factors for predicting the early

Overview of genetic and epigenetic alterations in the pathogenesis of esophagogastric junctional adenocarcinoma and esophageal adenocarcinoma: recent fi ndings by next generation sequencing

Esophagogastric junctional adenocarcinoma is commonly treated as esophageal adenocarcinoma(EAC)and has dramatically increased in Western countries for several decades.The similar trend has been observed in Asian countries(not in China).Barrett’s esophagus(BE)is a widely accepted precursor of EAC.Recent advances of next-generation sequencing could provide researchers with a better understanding of genetic and epigenetic alterations in the carcinogenesis of EAC.In this review,we have summarized the recently reported major genetic and epigenetic alterations in both BE and EAC.Sonic hedgehog/bone morphogenetic protein axis,which is a key signaling for esophageal development,plays an important role in BE intestinal metaplasia.Single nucleotide polymorphisms related to esophageal organogenesis,such as FOXF1 and FOXP3,are frequently detected in BE patients.During the progression of BE to adenocarcinoma,lacking of normal function of TP53 and CDKN2A by loss of heterozygosity(LOH),mutation,or promoter methylation has been frequently observed.LOH at 9p(coding CDKN2A)is an earlier event to EAC carcinogenesis compared to that at 17q(coding TP53)LOH.In order to further elucidate the pathogenesis of BE and EAC,it will be necessary to analyze these genetic/epigenetic alterations in combination with clinical data in a large-scale cohort.

Risk factors for anastomotic leakage after gastrectomy for Siewert type Ⅱ/Ⅲ adenocarcinoma of the esophagogastric junction:a retrospective case-control study

Objective:To identify risk factors for anastomotic leakage after gastrectomy in patients with Siewert type II/III adenocarcinoma(AEG)of the esophagogastric junction.Methods:This was a retrospective case-control study of 903 patients with Siewert type II/III AEG treated from January 2012 to January 2015 at the Shanxi Cancer Hospital in China.All patients underwent gastrectomy,and their clinical characteristics were analyzed to identify associations with anastomotic leakage.Independent risk factors were identified by binary logistic regression.The 2-year disease-free survival was calculated and compared between patients with anastomotic leakage and control patients.The study was approved by the Institutional Review Board of Shanxi Medical University(approval No.2014-09-39)on September 19,2014.Results:Out of the 903 patients were included in the study,80(8.86%,80/903)experienced anastomotic leakage.The mortality rate attributed to anastomotic leakage was 8.75%(7/80).Logistic regression analysis revealed that preoperative hypoalbuminemia(odds ratio(OR)=3.249,95%confidence interval(CI):1.569-6.725,P=0.002),type of reconstruction(OR=1.795,95%CI:1.026-3.142,P=0.040),and combined organ resection(OR=1.807,95%CI:1.069-3.055,P=0.027)were independent risk factors for anastomotic leakage.Conclusion:Preoperative hypoalbuminemia,type of reconstruction,and combined organ resection were identified as risk factors for anastomotic leakage in patients undergoing gastrectomy for Siewert type Ⅱ/Ⅲ AEG.

对比经口置入砥钉座方法进行食管空肠吻合与使用圆形吻合器进行腔外吻合应用于Siewert 2型食管胃结合部腺癌全胃切除后消化道重建的安全性

背景:对于近端胃癌全胃切除后消化道重建,采用经口置入砥钉座方法进行腔内食管空肠吻合已被证明是安全可行的。但尚未见到该方法用于Siewert 2型食管胃结合部腺癌(AEG)的评估报道。方法:2008年1月至2016年12月间,428例连续胃癌患者在广州南方医院接受腹腔镜全胃切除术,其中98例被归为Siewert 2型AEG。在98例AEG患者中,27例采用经口置入砥钉座方法进行腔内食管空肠吻合(经口组),71例采用圆形吻合器进行腔外食管空肠吻合(腔外组)。在基于吻合口漏危险因素进行1:1的倾向评分匹配后,26对匹配患者纳入分析。比较两组患者术后30天的安全性。结果:两组患者基线资料均衡。手术时间、消化道重建耗时、淋巴结清扫数量、近切缘长度、术中失血量、术中并发症发生率和术后恢复时间两组差异均无统计学意义。经口组相较腔外组,砥钉座置入时间更短(平均数:9.7 vs 13.4 min,P<0.001),手术切口更短(中位数:5.5 vs 7.0 cm,P<0.001)。术后并发症发生率两组差异无统计学意义(26.9%vs 23.1%,P¼0.749),并发症严重程度亦无显著差异(P¼0.939)。结论:采用经口置入砥钉座方法进行腔内食管空肠吻合,用以简化并优化Siewert 2型AEG患者全胃切除术后的消化道重建,是潜在安全的。