Preoperative BChE serves as a prognostic marker in patients with resectable AEG after neoadjuvant chemotherapy.

BACKGROUND: Diminished systemic serum butyrylcholinesterase (BChE), a biomarker for chronic inflammation, cachexia, and advanced tumor stage, has shown to play a prognostic role in various malignancies. The aim of this study was to investigate the prognostic value of pretherapeutic BChE levels in patients with resectable adenocarcinoma of the gastroesophageal junction (AEG), treated with or without neoadjuvant therapy. METHODS: Data of a consecutive series of patients with resectable AEG at the Department for General Surgery, Medical University of Vienna, were analyzed. Preoperative serum BChE levels were correlated to clinic-pathological parameters as well as treatment response. The prognostic impact of serum BChE levels on disease-free (DFS) and overall survival (OS) was evaluated by univariate and multivariate cox regression analysis, and Kaplan-Meier curves used for illustration. RESULTS: A total of 319 patients were included in this study, with an overall mean (standard deviation, SD) pretreatment serum BChE level of 6.22 (± 1.91) IU/L. In univariate models, diminished preoperative serum BChE levels were significantly associated with shorter overall (OS, p < 0.003) and disease-free survival (DFS, p < 0.001) in patients who received neoadjuvant treatment and/or primary resection. In multivariated analysis, decreased BChE was significantly associated with shorter DFS (HR: 0.92, 95% CI: 0.84-1.00, p 0.049) and OS (HR: 0.92, 95% CI: 0.85-1.00, p < 0.49) in patients receiving neoadjuvant therapy. Backward regression identified the interaction between preoperative BChE and neoadjuvant chemotherapy as a predictive factor for DFS and OS. CONCLUSION: Diminished serum BChE serves as a strong, independent, and cost-effective prognostic biomarker for worse outcome in patients with resectable AEG who had received neoadjuvant chemotherapy.

Near infrared ray-guided surgery using Firefly technology of the daVinci Xi system and intraoperative upper gastrointestinal endoscopy for subtotal gastrectomy and surgery for cancer of the gastroesophageal junction.

BACKGROUND: In gastrectomies, especially subtotal gastrectomies and operations on the gastroesophageal junction, identifying the exact location of the tumor and establishing the appropriate resection line is very important. Accurate resection lines have a major impact on the preservation of organ function and curability. Preservation of as much as possible of the remaining stomach, including the fornix, may be an important surgical goal for maintaining an adequate postoperative quality of life. In adenocarcinoma of the gastroesophageal junction, the height of the esophageal dissection may affect reconstruction of the transhiatal approach. METHODS: We perform a new technique, near infrared ray-guided surgery, for the accurate localization of a tumor using the Firefly technology of the daVinci Xi system and intra-operative upper gastrointestinal endoscopy. We used this new technique for cases of upper gastric cancer or adenocarcinoma of the gastroesophageal junction. In this retrospective study, we examined to determine the extent (mm) of the tumor invasion of the esophagus, visualization of near infrared ray contained within endoscopic light, and distance from the proximal margin of the tumor to the surgical cut line on rapid histopathology and in the permanent preparation, including the operative videos and extracted specimens. RESULTS: We performed near infrared ray-guided surgery for 12 patients with gastric cancer or adenocarcinoma of the gastroesophageal junction, and the near infrared ray was clearly seen as green light with Firefly mode in all the patients. Near infrared ray-guided surgery was useful for obtaining localization of the tumor. In addition, it was possible to resect organ with adequate margins from tumor. Rapid intraoperative histopathological examinations confirmed that the resected specimens had negative margins. None of the patients required additional resection. CONCLUSIONS: We believe that because near infrared ray-guided surgery can provide an accurate resection line, it will be useful for the resection of upper gastric cancer and adenocarcinoma of the gastroesophageal junction. It will also provide patients with a good postoperative quality of life after surgery.

RACE-trial: neoadjuvant radiochemotherapy versus chemotherapy for patients with locally advanced, potentially resectable adenocarcinoma of the gastroesophageal junction - a randomized phase III joint study of the AIO, ARO and DGAV.

BACKGROUND: Despite obvious advances over the last decades, locally advanced adenocarcinomas of the gastroesophageal junction (GEJ) still carry a dismal prognosis with overall 5-year survival rates of less than 50% even when using modern optimized treatment protocols such as perioperative chemotherapy based on the FLOT regimen or radiochemotherapy. Therefore the question remains whether neoadjuvant chemotherapy or neoadjuvant radiochemotherapy is eliciting the best results in patients with GEJ cancer. Hence, an adequately powered multicentre trial comparing both therapeutic strategies is clearly warranted. METHODS: The RACE trial is a an investigator initiated multicenter, prospective, randomized, stratified phase III clinical trial and seeks to investigate the role of preoperative induction chemotherapy (2 cycles of FLOT: 5-FU, leucovorin, oxaliplatin, docetaxel) with subsequent preoperative radiochemotherapy (oxaliplatin weekly, 5-FU plus concurrent fractioned radiotherapy to a dose of 45 Gy) compared to preoperative chemotherapy alone (4 cycles of FLOT), both followed by resection and postoperative completion of chemotherapy (4 cycles of FLOT), in the treatment of locally advanced, potentially resectable adenocarcinoma of the gastroesophageal junction. Patients with cT3-4, any N, M0 or cT2 N+, M0 adenocarcinoma of the GEJ are eligible for inclusion. The RACE trial aims to enrol 340 patients to be allocated to both treatment arms in a 1:1 ratio stratified by tumour site. The primary endpoint of the trial is progression-free survival assessed with follow-up of maximum 60 months. Secondary endpoints include overall survival, R0 resection rate, number of harvested lymph nodes, site of tumour relapse, perioperative morbidity and mortality, safety and toxicity and quality of life. DISCUSSION: The RACE trial compares induction chemotherapy with FLOT followed by preoperative oxaliplatin and 5-Fluorouracil-based chemoradiation versus preoperative chemotherapy with FLOT alone, both followed by surgery and postoperative completion of FLOT chemotherapy in the treatment of locally advanced, non-metastatic adenocarcinoma of the GEJ. The trial aims to show superiority of the combined chemotherapy/radiochemotherapy treatment, assessed by progression-free survival, over perioperative chemotherapy alone. TRIAL REGISTRATION: ClinicalTrials.gov ; NCT04375605 ; Registered 4th May 2020.

NeoFLOT: Multicenter phase II study of perioperative chemotherapy in resectable adenocarcinoma of the gastroesophageal junction or gastric adenocarcinoma-Very good response predominantly in patients with intestinal type tumors.

Perioperative treatment is a standard of care in locally advanced gastroesophageal cancer (GEC) (gastric adenocarcinoma and gastroesophageal junction (GEJ) adenocarcinoma). While preoperative treatment can be applied to the majority of patients, postoperative chemotherapy can be given only to a fraction. The NeoFLOT-study therefore investigates the application of prolonged neoadjuvant chemotherapy (NACT). Patients with T3, T4, and/or node-positive adenocarcinoma (GEC) were eligible for this multicenter phase II trial. NACT consisted of 6 cycles of oxaliplatin 85 mg/m(2) , leucovorin 200 mg/m(2) , 5-fluorouracil 2600 mg/m(2) and docetaxel 50 mg/m(2) (FLOT) applied q 2 wks. Application of adjuvant chemotherapy was explicitly not part of the protocol. R0-resection rate was evaluated as a primary endpoint. Of 59 enrolled patients, 50 patients underwent surgery and were assessable for the primary endpoint. R0-resection rate was 86.0% (43/50). Pathologic complete response (pCR) was 20.0% (10/50) and a further 20% (10/50) of patients achieved near complete histological remission (<10% residual tumor). Among these very good responders, 85% (17/20) had intestinal type tumors, 10% (2/20) had diffuse and 5% (1/20) had mixed type tumors. After 3 cycles of NACT, 6.9% (4/58) of patients developed progressive disease. Median disease-free survival was 32.9 months. The 1-year survival-rate was 79.3%. Grade 3-4 toxicities included neutropenia 29.3%, febrile neutropenia 1.7%, diarrhea 12.1% and mucositis 6.9%. This study indicates that intensified NACT with 6 cycles of FLOT is highly effective and tolerable in resectable GEC. Very good response (pCR and <10% residual tumor) was predominantly observed in patients with intestinal type tumors.

Cystathionine ß-synthase expression correlates with tumor development and poor prognosis in patients with adenocarcinoma of the gastroesophageal junction.

OBJECTIVES: To reveal the expression level of cystathionine ß-synthase (CBS) in adenocarcinoma of esophagogastric junction (AEG) and discuss the relationship between CBS expression level and tumor microvascular density (MVD), clinical features and prognosis. METHODS: Paraffin samples from 214 patients with AEG were selected to make pathological microchips. Immunohistochemistry was performed based on the microchips to detect the expression level of CBS and microvascular density (MVD) in cancer tissues and adjacent control tissues. Relationships between expression level of CBS and MVD, clinical characteristics and prognosis were analyzed. RESULTS: In total, 214 AEG cases were classified into three groups: CBS negative staining (n=26), low staining (n=44), and high staining (n=144). Quantitative alterations in CBS and CD31 expression were explored using immunohistochemistry. The 5-year recurrence rate of enrolled patients was followed up and found that CBS expression was significantly increased in tumor tissue compared with adjacent non-tumor tissue (P<0.0001). There were significant differences in microvascular density between the groups with negative and high CBS staining (P<0.0001), and between the groups with low and high CBS staining (P<0.0001). Univariate analysis revealed significant differences in tumor stage (P<0.0001), T stage (P=0.008), N stage (P=0.028), differentiation degree (P=0.037), and 5-year survival (P=0.0034) among the three groups. Multivariate logic regression analysis showed that increased CBS scores were associated with an increased probability of 5-year recurrence (P=0.018). Finally, different CBS expression levels were associated with disease-free survival in AEG patients. CONCLUSIONS: CBS expression level is closely related to microvascular density and tumor stage in AEG. High level of CBS not only accelerates tumor angiogenesis but also affects patient's survival and prognosis.

Expression of programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand (PD-L1) in adenocarcinomas of the gastroesophageal junction change significantly after neoadjuvant treatment.

BACKGROUND: The effects of cytotoxic chemotherapy on the expression of programmed cell death 1 (PD-1) and its ligand (PD-L1) in cancer cells and peritumoral cells are unclear. The aim of this study was to investigate the impact of neoadjuvant chemotherapy on PD-1 and PD-L1 expression in adenocarcinomas of the gastroesophageal junction. METHODS: PD-1 and PD-L1 expression in cancer cells and tumor-infiltrating lymphocytes in paired diagnostic biopsies and surgical specimens from patients with pretreated and curatively resected adenocarcinomas of the gastroesophageal junction were evaluated by immunohistochemistry. RESULTS: Paired tumor samples were available from 40 patients. PD-1 expression in cancer cells (p < 0.001; Exact Symmetry Test) and tumor-infiltrating lymphocytes (p < 0.001; Exact Symmetry Test) increased significantly after neoadjuvant therapy. Furthermore, we observed a significant decrease in PD-L1 expression in cancer cells (p = 0.003) after neoadjuvant therapy was observed. CONCLUSION: In this study we could show that tumor-cell expression of PD-1 and PD-L1 was significantly altered in patients with adenocarcinomas of the gastroesophageal junction after receiving neoadjuvant chemotherapy. Based on these observations, patients might profit from the combined use of cytotoxic chemotherapy and the blockade of the PD-1 axis.

Programmed death ligand 2 expression plays a limited role in adenocarcinomas of the gastroesophageal junction after preoperative chemotherapy.

BACKGROUND: The effects of cytotoxic chemotherapy on the expression of programmed death ligand 2 (PD-L2) are unknown and little is known about how the tumor microenvironment changes following neoadjuvant chemotherapy in locally advanced gastroesophageal adenocarcinomas (AEG). Recently, a number of studies reported that cytotoxic chemotherapy affects the expression levels of programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1). Regarding PD-L2, the second known ligand of PD­1, no data on potential changes in expression patterns in patients with preoperatively treated AEG are available. The aim of this study was to investigate the impact of cytotoxic chemotherapy on PD-L2 expression in patients with resectable AEG. METHODS: Consecutive patients with locally advanced AEG treated with preoperative cytotoxic chemotherapy were included. PD-L2 expression by cancer cells (CCs) and tumor-infiltrating lymphocytes (TILs) was investigated in samples of paired diagnostic biopsies and resected tumor specimens by immunohistochemistry using two different anti-PD-L2 antibodies. RESULTS: Included were 40 patients with AEG and available paired tumor tissue samples. PD-L2 expression was observed in one diagnostic biopsy sample by CCs and in one diagnostic biopsy sample by TILs. There was no difference concerning the expression levels measured by the two antibodies. CONCLUSION: In contrast to previously published studies reporting PD-L2 expression rates of up to 50% in AEGs, in our cohort, PD-L2 expression seems to play no significant role in AEG.

[Therapeutic approach in oligometastatic gastric and esophageal cancer]. / Therapeutisches Vorgehen beim oligometastasierten Magen- und Ösophaguskarzinom.

The therapeutic approach to patients with oligometastatic gastric cancer and esophageal cancer is currently undergoing a shift towards a more aggressive therapy including surgical resection. In the current German S3 guidelines surgical treatment of metastatic disease is not recommended; however, nowadays interdisciplinary tumor boards have to evaluate such patients increasingly more often. On an individual basis a radical surgical resection of the primary tumor and the metastases is considered and performed in patients who respond well to multimodal chemotherapy concepts. In this review article the currently available data from the literature are discussed and a foundation for individually extended surgical approaches is presented. Together with the currently available results of the FLOT 3 study and the mostly retrospective studies, it seems to be possible to identify patients who would profit from such an aggressive treatment. In the future randomized prospective studies, such as the RENAISSANCE/FLOT 5 study and the GASTRIPEC study will have to evaluate whether an aggressive surgical therapy within multimodal therapy concepts of metastatic gastric and esophageal carcinomas is warranted.

Explored Risk Factors for Lymph Node Metastasis with Siewert II/III Adenocarcinoma of the Gastroesophageal Junction.

AIM: To explore the risk factors and prognosis for lymphatic metastasis (LNM) in patients with Siewert II/III adenocarcinoma of the gastroesophageal junction (AEG). PATIENTS AND METHODS: This study retrospectively reviewed 49 patients with Siewert II/III AEG. Clinical characteristics and pathological features were analyzed by the Chi-square the and binary logistic regression. Survival data were analyzed using the Kaplan-Meier method. RESULTS: LNM frequency was found in lymph nodes No.1, No.2, No.3, No.7, No.11 and No.110. The results revealed that depth of infiltration, neoplasms by histological type and lymphatic embolus were independent risk factors for LNM. The 1- and 3-year survival of patients without LNM were both 100%, while patients with LNM had 70% and 60% survival, respectively. Although the differences were not statistically significant, survival rate with negative lymph nodes was higher than in patients with LNM. CONCLUSION: Total gastrectomy combined with D2 No.110 lymphadenectomy might improve the prognosis for LNM patients.

Rules and prognosis analysis for lymph node metastasis in patients with Siewert Ⅱ and Ⅲ adenocarcinoma of the gastroesophageal junction / 国际外科学杂志

Objective To analyze the related rules and prognosis analysis for lymphatic metastasis in patients for Siewert Ⅱ and Ⅲ adenocarcinoma of the gastroesophageal junction.Methods This study retrospectively reviewed 65 patients who underwent radical surgery for Siewert Ⅱ and Ⅲ adenocarcinoma of the gastroesophageal junction in Beijing Friendship Hospital between July 2013 and March 2017.The primary indicators were sex,age,tumor site,tumor size,macroscopic type,histological type,depth of invasion,operation,tumor emboli and carcinoma nodes.The clinical characteristics and pathological features were analyzed by using Logistic regression and Kaplan-Meier survival analysis.Follow-tup using outpatient examination and telephone interview was performed to detect patients' diseases and postoperative survival up to April 2017.Results Lymph node metastasis was observed in 41 of 65 patients (63.1％).Lymph node metastasis frequency was found in No.1,No.2,No.3,No.7,No.11 and No.110 lymph nodes.The incidences of those lymph node metastasis were 45.3％,32.5％,28.8％,22.5％,19.4％ and 8.2％.The metastasis rate of the tumors with diameter over 2 cm was higher than the tumors which were less than 2 cm (71.9％ vs 0;P =0.000);The observed rate of lymph node metastasis was 0,12.5％,69％,95.2％ in early cancer (T1) and advanced cancer (T2-T4) (P=0.000) respectively.The metastasis rate of highly differentiated Siewert Ⅱ and Ⅲ adenocarcinoma of the gastroesophageal junction was 45.2％ lower than poorly differentiated tumors 79.4％ (P =0.009).Thirty-three cases were found with lymphatic embolus,28 of them (84.8％) were found to be combined with lymph node metastasis among them (P =0.001).All the differences were statistically significant (P ＜ 0.05).The results of multivariable analyzed by binary logistic regression analysis revealed that neoplasms histologic type and lymphatic embolus were independent risk factors for lymph node metastasis of Siewert Ⅱ and Ⅲ adenocarcinoma of the gastroesophageal junction.Sixty-five patients were followed up for 1-45 months,with a median time of 18.81 months.Although there was no statistically significant difference,3 years-overall survival rate showed tumor without lymph node metastasis has better prognosis than with lymph node metastasis and early stage tumor also has better prognosis than advanced tumor.Conclusions Lymph node metastasis of Siewert Ⅱ and Ⅲ adenocarcinoma of the gastroesophageal junction is related with histological type of tumor and lymphatic embolus.For Siewert Ⅱ and Ⅲ adenocarcinoma of the gastroesophageal junction,the incidence of lymphatic metastasis were higher appear in abdominal cavity,which included No.1,No.2,No.3,No.7 and No.11;Meanwhile,the metastasis of mediastinal lymph node is given priority to No.110 lymph node.Therefore,radical total gastrectomy combined with standard D2 lymphadenectomy and No.110 lymphadenectomy are performed in order to improving the prognosis.For patients with lymph node metastasis and tumor in advanced stage,long-term prognosis remains to be further study.

The associat ion of Her-2 amplification and overexpression with clinicopathological faetures in adenocar-cinoma of the gastroesop hageal junction / 实用肿瘤学杂志

Objective To study the protein expression and gene amplification of human epidermal growth factor receptor-2(Her-2)in adenocarcinoma of the gastroesophageal junction and its association with the clinicopathological features .Methods Immunohistochemical method and fluorescence in situ hybridization ( FISH) were used to detect Her -2 expression and gene amplification in 80 surgically resected gastroesophageal junction cancer tissue .We further analyzed the relationship between the gastroesophageal junction cancer histolog -ical differentiation ,as well as depth of invasion ,clinical stage and lymph node metastasis .Results Her-2 am-plification of gastroesophageal junction carcinoma by FISH was 22.5%,while the overexpression by IHC was 15%.Her-2 gene amplification and protein overexpression were correlated with the differentiation ,clinical TNM stage,invasive depth and lymph node metastasis of the carcinoma (all P<0.05).Her-2 expression was not asso-ciated with the patients age,gender,invasive depth and lymph node metastasis(P<0.05).Conclusion Her -2 protein expression and gene amplification may be a prognostic indicator for the patients with gastroesophageal junction cancer .The joint detection of Her -2 protein expression level and the gene amplification can guide the prognosis and therapy for adenocarcinoma of the gastroesophageal junction .