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Summary: Evaluation of HER2 status and programmed death-ligand 1 (PD-L1) combined positive score (CPS) is mandatory in all patients with HER2-positive metastatic adenocarcinoma of the gastroesophageal junction (GEJ) not only to tailor first-line therapy but also to improve individual survival outcome. However, despite advances in the therapeutic management of metastatic adenocarcinoma of the GEJ, prognosis of these patients remains poor. We report a patient with HER2-positive metastatic adenocarcinoma of the GEJ who showed significant clinical and radiological benefit to HER2-directed therapy in the fifth-line therapeutic setting. [ABSTRACT FROM AUTHOR]

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • The introduction of immunotherapy represents a paradigm shift in treating cancer. • A number of studies described synergism between cytotoxic chemotherapy and PD-1/PD-L1 immunotherapy. • Our findings suggest that combining cytotoxic chemotherapy with checkpoint inhibitors represents an beneficial option for AEG patients. [ABSTRACT FROM AUTHOR]

Summary: 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 PD‑1, 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. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To systematically evaluate the efficacy of programmed death-1/programmed death ligand-1（ PD-1/PD-L1） monoclonal antibody in gastric cancer or adenocarcinoma of the gastroesophageal junction.METHODS: PubMed,Embase,the Cochrane Library database and abstracts of American society of clinical oncology（ ASCO） conferences in the past three years,and European society for medical oncology（ ESMO） conferences in 2020 were retrieved to collect the prospective studies,phase Ⅱ and phase Ⅲ clinical trials( the study group was treated with PD-1/PD-L1 monoclonal antibody alone or in combination with chemotherapy,while the control group received chemotherapy or placebo. The retrieval deadline was Sept. 26 th,2020. The efficacy of different treatment regimens（ PD-1/PD-L1 monoclonal antibody treatment group compared with chemotherapy group,PD-1/PD-L1 monoclonal antibody treatment + chemotherapy group compared with chemotherapy group,and PD-1/PD-L1 monoclonal antibody treatment group compared with placebo group） was assessed by subgroup analysis,and forest plotting was performed by Stata SE 12 software. RESULTS: Seven clinical trials were ultimately enrolled,including three original papers,two abstracts of ASCO conferences and two abstracts of ESMO conferences.（ 1） The differences in overall survival（ OS）（ HR = 0. 96,95% CI = 0. 87-1. 07,P = 0. 451） and objective response rate（ ORR）（ RR = 0. 65,95% CI = 0. 39-1. 09,P = 0. 102） between the PD-1/PD-L1 monoclonal antibody treatment group alone and the chemotherapy group were not statistically significant,yet the difference in progression free survival（ PFS） between two groups was statistically significant（ HR = 1. 45,95% CI = 1. 17-1. 81,P = 0. 001）.（ 2） The differences of OS（ HR = 0. 84,95% CI = 0. 76-0. 94,P = 0. 001）,PFS（ HR = 0. 78,95% CI = 0. 70-0. 86,P = 0. 000） and ORR（ RR = 1. 24,95% CI = 1. 10-1. 39,P = 0. 000） between the PD-1/PD-L1 monoclonal antibody treatment + chemotherapy group and the chemotherapy group were statistically significant.（ 3） The differences of OS（ HR = 0. 63,95% CI = 0. 51-0. 78,P = 0. 000）,PFS（ HR = 0. 60,95% CI = 0. 49-0. 75,P = 0. 000） and ORR（ RR = 29. 93,95% CI = 1. 84-485. 72,P = 0. 017）between the PD-1/PD-L1 monoclonal antibody treatment group and the placebo group were statistically significant.CONCLUSIONS: The results of this study suggest that PD-1/PD-L1 monoclonal antibody combined with chemotherapy may benefit patients with advanced gastric cancer or adenocarcinoma of the gastroesophageal junction.Compared with placebo,PD-1/PD-L1 monoclonal antibody alone also benefits patients with advanced gastric cancer or adenocarcinoma of the gastroesophageal junction. However,compared with chemotherapy,patients with advanced gastric cancer or adenocarcinoma of the gastroesophageal junction may not get a more significant treatment effect from PD-1/PD-L1 monoclonal antibody,and more evidence is needed to confirm these findings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV)-associated gastric carcinomas (GC) represent a distinct and well-recognized subtype of gastric cancer with a prevalence of around 10% of all GC. In contrast, EBV has not been reported to play a major role in esophageal adenocarcinomas (EAC) and adenocarcinomas of the gastro-esophageal junction (GEJ). We report our experiences on EBV in collections of gastro-esophageal adenocarcinomas from two surgical centers and discuss the current state of research in this field. Tumor samples from 465 primary resected gastro-esophageal adenocarcinomas (118 EAC, 73 GEJ and 274 GC) were investigated. Presence of EBV was determined by EBV-encoded small RNAs (EBER) in situ hybridization. Results were correlated with pathologic parameters (UICC pTNM category, Her2 status, tumor grading) and survival. EBER positivity was observed in 14 cases. None of the EAC were positive for EBER. In contrast, we observed EBER positivity in 2/73 adenocarcinomas of the GEJ (2.7%) and 12/274 GC (4.4%). These were of intestinal type (7 cases) or unclassifiable (6 cases), while only one case was of diffuse type according to the Lauren classification. No association between EBV and pT, pN or tumor grading was found, neither was there a correlation with clinical outcome. None of the EBER positive cases were Her2 positive. In conclusion, EBV does not seem to play a role in the carcinogenesis of EAC. Moreover adenocarcinomas of the GEJ show lower rates of EBV positivity compared to GC. Our data only partially correlate with previous reports from the literature. This highlights the need for further research on this distinct entity. Recent reports, however, have identified specific epigenetic and genetic alterations in EBV-associated GC, which might lead to a distinct treatment approach for this specific subtype of GC in the future.

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/m2, leucovorin 200 mg/m2, 5-fluorouracil 2600 mg/m2 and docetaxel 50 mg/m2 (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. [ABSTRACT FROM AUTHOR]

Objectives: To reveal the expression level of cystathionine β-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., Competing Interests: None., (AJTR Copyright © 2022.)

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., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., (© 2014 UICC.)