Esophagogastric Junction Carcinoma Research Articles

Cytokine release syndrome following COVID-19 infection during treatment with nivolumab for cancer of esophagogastric junction carcinoma: a case report and review

BackgroundCytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ failure, which is triggered by immunotherapy or certain infections. Immune checkpoint inhibitors rarely cause immune-related adverse event- cytokine release syndrome (irAE-CRS). This article presents a case report of irAE-CRS triggered by coronavirus disease 2019 (COVID-19).Case presentationA 60-year-old man with type 2 diabetes received nivolumab treatment for esophagogastric junction carcinoma and experienced two immune-related adverse events: hypothyroidism and skin disorder. Eleven days before his visit to our hospital, he had a fever and was diagnosed with COVID-19. Five days before his visit, he developed a fever again, along with general malaise, water soluble diarrhea, and myalgia of the extremities. On admission, the patient was in a state of multiple organ failure, and although the source of infection was unknown, a tentative diagnosis of septic shock was made. The patient's condition was unstable despite systemic management with antimicrobial agents, high-dose vasopressors, and intravenous fluids. We suspected CRS due to irAE (irAE-CRS) based on his history of nivolumab use. Steroid pulse therapy (methylprednisolone 1 g/day) was started, and the patient temporarily recovered. However, his respiratory condition worsened; consequently, he was placed on a ventilator and tocilizumab was added to the treatment. His muscle strength recovered to the point where he could live at home, and was subsequently discharged.ConclusionIn patients previously treated with immune checkpoint inhibitors, irAE-CRS should be considered as a differential diagnosis when multiple organ damage is observed in addition to inflammatory findings. It is recommended to start treatment with steroids; if the disease is refractory, other immunosuppressive therapies such as tocilizumab should be introduced as early as possible.

278. PROPOSED REVISION TO THE DESCRIPTION OF T3 FOR ESOPHAGEAL CANCER: REMOVAL OF “ADVENTITIA”

Abstract Background T3 is an important depth for esophageal cancer to target for surgical cure. According to the Union for International Cancer Control (UICC), T3 is defined as tumor invading the adventitia. However, it remains unclear what structures the adventitia refers to. In fact, tumors that do not directly invade adjacent organs have been classified as T3, even if they extend through the adventitia. Furthermore, in tumors arising at the esophagogastric junction (EGJ), it is difficult to determine the border with the subserosa that defines T3 of the stomach. Our aim was to revise the description of T3 in esophageal cancer. Methods The Union for International Cancer Control T-classification was reviewed from a histologic, pathologic, and embryologic perspective. Analysis of endoscopic ultrasound images, review of intraoperative images, and detailed observation of surgical specimens were followed by a review of the literature. Results Histologically, the adventitia is the extramural adipose connective tissue of the digestive tract and serves as a conduit for blood vessels, lymphatics, and nerves. The esophageal adventitia is further surrounded by connective tissue of adjacent organs, such as the tissue around the trachea, the tissue around the descending thoracic aorta, the pulmonary ligament, and the tissue on the diaphragm (Fig. 1a). In the 2022 revision of the Japanese Esophageal Society, resectable borderline cases in which adjacent organ invasion cannot be excluded by preoperative imaging were subclassified as borderline resectable T3 (T3br). From another perspective, this is a clinically reasonable criterion that not only adventitial invasion, but also invasion of connective tissue associated with adjacent organs is classified as T3. Beyond the EGJ, the adventitia is covered by mesothelium in the peritoneal cavity and leads to the subserosa. Endoscopic ultrasound revealed the fatty tissue of the adventitia as a highly echogenic layer on the surface of the muscularis propria, which continues uninterrupted beyond the EGJ into the stomach, indicating that the adventitia is connected to the subserosa. Intraoperative images showed that the descending posterior trunk of the vagus nerve and its associated vessels pass through the adipose tissue surrounding the esophagus in the esophageal hiatus (Fig. 1b). Thus, the ambiguity in the T-classification of esophageal cancer is not resolved as long as T3 is defined by the adventitia. In practice, however, physicians may have classified tumors as T2 if confined to the muscularis propria, T4 if invading adjacent organs, and T3 if neither. Conclusion We suggest that the description of T3 esophageal cancer be revised to read "tumor extends through the muscularis propria" rather than using the term "adventitia". This revision would clarify the depth criteria for determining the indication for surgical treatment not only for esophageal cancer, but also for EGJ carcinoma where the tumor center overlaps the gastric side.

Gender medicine in diseases of the upper gastrointestinal tract

Benign and malignant diseases of the upper gastrointestinal tract show gender-specific differences. The frequent gastroesophageal reflux disease is aprime example: men have an erosive reflux disease more often than women and are also younger at the time of onset. The rate of progression to a metaplastic Barrett's esophagus is also higher in men. In the case of achalasia, there are indications that surgical treatment by laparoscopic Heller's myotomy and semifundoplication 180° according to Dor leads to amarkedly better improvement in the symptoms in women compared to men, although they showed amore pronounced dilation of the tubular esophagus. The female hormone status influences the localization and histopathology of adenocarcinoma of the esophagogastric junction and gastric carcinoma. Premenopausal and postmenopausal carcinomas differ significantly in women. In addition, high microsatellite instability (MSI high) is more frequent in women and is associated with agenerally significantly better prognosis. The MSI high gastric carcinomas of women show better survival than MSI high carcinomas of men. The future inclusion of gender-specific aspects in studies of the upper gastrointestinal tract is desirable in order to generate adequate data and to enable differentiated treatment stratification in the future.

Characteristics of auto-quantified tumor-infiltrating lymphocytes and the prognostic value in adenocarcinoma of the esophagogastric junction, gastric adenocarcinoma, and esophageal squamous cell carcinoma.

Adenocarcinoma of the esophagogastric junction (AEGJ) with a specific pathological profile and poor prognosis has limited therapeutic options. Previous studies have found that TILs exhibit distinct characteristics in different tumors and are correlated with tumor prognosis. We established cellular training sets to obtain auto-quantified TILs in pathological images. And we compared the characteristics of TILs in AEGJ with those in esophageal squamous cell carcinoma (ESCC) and gastric adenocarcinoma (GAC) to gain insight into the unique immune environments of these three tumors and investigate the prognostic value of TILs in these three tumors. Utilizing a case-control study design, we analyzed 214 AEGJ, 256 GAC, and 752 ESCC cases. The TCGA dataset was used to validate prognostic value of auto-quantified TILs. The specific cellular training sets were established by experienced pathologists to determine TILs counts. Kruskal-Wallis test and multi-variable linear regression were conducted to explore TILs characteristics. Survival analyses were performed with Kaplan-Meier method and Cox proportional hazards model. The three cellular training sets of these cancers achieved a classification accuracy of 87.55 at least. The median auto-quantified TILs of AEGJ, GAC, and ESCC cases were 4.82%, 1.92%, and 0.12%, respectively. The TILs demonstrated varied characteristics under distinctive clinicopathological traits. The higher TILs proportion was associated with better prognosis in esophagogastric cancers (all P < 0.05) and was an independent prognostic biomarker on AEGJ in both datasets (Taixing: HR = 0.965, 95% CI = 0.938-0.994; TCGA: HR = 0.811, 95% CI = 0.712-0.925). We found variations in TILs across ESCC, GAC, and AEGJ, as assessed by image processing algorithms. Additionally, TILs in these three cancers are an independent prognostic factor. This enhances our understanding of the unique immune characteristics of the three tumors, improving patient outcomes.

Evaluating the use of three-dimensional reconstruction visualization technology for precise laparoscopic resection in gastroesophageal junction cancer.

Laparoscopic gastrectomy for esophagogastric junction (EGJ) carcinoma enables the removal of the carcinoma at the junction between the stomach and esophagus while preserving the gastric function, thereby providing patients with better treatment outcomes and quality of life. Nonetheless, this surgical technique also presents some challenges and limitations. Therefore, three-dimensional reconstruction visualization technology (3D RVT) has been introduced into the procedure, providing doctors with more comprehensive and intuitive anatomical information that helps with surgical planning, navigation, and outcome evaluation. To discuss the application and advantages of 3D RVT in precise laparoscopic resection of EGJ carcinomas. Data were obtained from the electronic or paper-based medical records at The First Affiliated Hospital of Hebei North University from January 2020 to June 2022. A total of 120 patients diagnosed with EGJ carcinoma were included in the study. Of these, 68 underwent laparoscopic resection after computed tomography (CT)-enhanced scanning and were categorized into the 2D group, whereas 52 underwent laparoscopic resection after CT-enhanced scanning and 3D RVT and were categorized into the 3D group. This study had two outcome measures: the deviation between tumor-related factors (such as maximum tumor diameter and infiltration length) in 3D RVT and clinical reality, and surgical outcome indicators (such as operative time, intraoperative blood loss, number of lymph node dissections, R0 resection rate, postoperative hospital stay, postoperative gas discharge time, drainage tube removal time, and related complications) between the 2D and 3D groups. Among patients included in the 3D group, 27 had a maximum tumor diameter of less than 3 cm, whereas 25 had a diameter of 3 cm or more. In actual surgical observations, 24 had a diameter of less than 3 cm, whereas 28 had a diameter of 3 cm or more. The findings were consistent between the two methods (χ2 = 0.346, P = 0.556), with a kappa consistency coefficient of 0.808. With respect to infiltration length, in the 3D group, 23 patients had a length of less than 5 cm, whereas 29 had a length of 5 cm or more. In actual surgical observations, 20 cases had a length of less than 5 cm, whereas 32 had a length of 5 cm or more. The findings were consistent between the two methods (χ2 = 0.357, P = 0.550), with a kappa consistency coefficient of 0.486. Pearson correlation analysis showed that the maximum tumor diameter and infiltration length measured using 3D RVT were positively correlated with clinical observations during surgery (r = 0.814 and 0.490, both P < 0.05). The 3D group had a shorter operative time (157.02 ± 8.38 vs 183.16 ± 23.87), less intraoperative blood loss (83.65 ± 14.22 vs 110.94 ± 22.05), and higher number of lymph node dissections (28.98 ± 2.82 vs 23.56 ± 2.77) and R0 resection rate (80.77% vs 61.64%) than the 2D group. Furthermore, the 3D group had shorter hospital stay [8 (8, 9) vs 13 (14, 16)], time to gas passage [3 (3, 4) vs 4 (5, 5)], and drainage tube removal time [4 (4, 5) vs 6 (6, 7)] than the 2D group. The complication rate was lower in the 3D group (11.54%) than in the 2D group (26.47%) (χ2 = 4.106, P < 0.05). Using 3D RVT, doctors can gain a more comprehensive and intuitive understanding of the anatomy and related lesions of EGJ carcinomas, thus enabling more accurate surgical planning.

Quality control of digestive tract reconstruction after proximal gastrectomy

With the increasing incidence of esophagogastric junction carcinoma, the application rate of proximal gastrectomy has been rising annually. There is a wide variety of methods for digestive tract reconstruction after proximal gastrectomy, and some of these reconstruction methods have been introduced relatively recently, with limited clinical experience, which led to a lack of standardization. Such a situation will inevitably result in inconsistent clinical outcomes of proximal gastrectomy with digestive tract reconstruction. To promote the standardization of digestive tract reconstruction after proximal gastrectomy, improve the clinical efficacy of proximal gastrectomy, and reduce the occurrence of postoperative complications, this article elaborates on the indications, surgical steps and technical points of the four methods after proximal gastrectomy recommended by the "Chinese consensus on digestive tract reconstruction after proximal gastrectomy (2020 edition)", such as double tract, side overlap, double flaps and gastric tube reconstruction, providing guidance for the application of digestive tract reconstruction after proximal gastrectomy.

Ten-year overall survival of localized lower thoracic and esophagogastric junction carcinoma receiving trimodality therapy: A National Cancer Database analysis.

278 Background: Trimodality therapy, consisting of chemotherapy and radiation followed by esophagectomy, represents the prevailing standard of care for most patients with localized lower thoracic and esophagogastric junction (EGJ) carcinoma. However, robust data reporting the survival of this patient group treated in the real-world setting is lacking. The primary objective of the current study was to comprehensively analyze the long-term survival of this patient population receiving treatment in a real-world setting and the variables that significantly influence the survival. Methods: We identified adult patients in the National Cancer Database with localized (cT1N+M0 or cT2-T4N+/-M0) lower thoracic or EGJ adenocarcinoma (AC) or squamous cell carcinoma (SCC) receiving trimodality therapy between 2004 and 2020 with multi-agent chemotherapy and ≥ 4139 cGy of radiation followed by esophagectomy. The primary endpoint of the analysis was overall survival (OS), estimated using the Kaplan-Meier method. The impact of clinical and demographic features on OS was determined using the log-rank test. We performed a multivariable (MV) Cox analysis to evaluate the independent association of clinical and demographic variables on OS (data presented as hazard ratio [HR] and 95% Confidence Interval [CI]). Results: The analysis included 21,965 patients, characterized by a median age of 63 years, predominance of males (85.9%), non-Hispanic white patients (89.4%), and AC histology (93.6%). Most patients had T2/T3 tumors (87.3%) and regional lymph node (LN) involvement (62.1%). The 10-year OS for the entire cohort was 27.6% (95% CI, 26.8%-28.5%), with a median OS of 40.7 months (95% CI, 39.7-41.6). For patients aged ≤ 65, the 10-year OS was 31.2% (95% CI, 30.2%-32.3%), with a median OS of 44.1 months (95% CI, 42.8-45.5). On MV analysis, the following factors were associated with inferior OS with CI in the parenthesis: age ≥ 66 years (1.17, 1.11-1.22); male gender (1.13, 1.08-1.19); histology, AC vs. SCC (1.19, 1.10-1.28); T4 vs. T1-T3 tumor stage (1.20, 1.07-1.34); lymph node involvement (1.22, 1.18-1.27); Charlson-Deyo score ≥ 2 (1.23, 1.15-1.32); uninsured vs private insurance (1.20, 1.05-1.36); and low-volume facility (1.08, 1.01-1.16). Furthermore, patients treated after 2012 (2013-2019) had modestly improved OS (0.87, 0.84-0.90), perhaps reflecting the impact of the CROSS trial result published in 2012. Conclusions: This study illustrates the grim long-term survival of patients with localized lower thoracic and EGJ cancer undergoing standard trimodality therapy, underscoring the urgent necessity for innovative therapeutic approaches for this patient group. The improvement in OS following the publication of the CROSS trial was modest.

Longitudinal Analysis of Circulating Tumor DNA and Detection of Tumor Genomic Alterations Using Liquid Biopsy in Patients with Locally Advanced Esophagogastric Carcinoma

For locally advanced esophageal (E), esophagogastric junction (EGJ), and gastric (G) carcinoma, the standard treatment is neoadjuvant chemoradiotherapy followed by surgery. The curative goal is to control the tumor locally, prevent regional recurrence, and prevent or delay metastatic progression. Up to one-third of patients will achieve complete pathologic response rate (pCR) under this treatment. Yet disease recurrence can occur in one-third of patients after definitive treatment. Our study provides real-world longitudinal data of liquid biopsy to analyze circulating tumor deoxyribonucleotide acid (ctDNA) for minimal residual disease (MRD) as an informative marker for early therapeutic response, detectable disease, and risk for recurrence. Furthermore, the liquid biopsy reveals variable tumor-specific sequence alterations. A total of 8 patients with newly diagnosed locoregional esophagogastric cancers were evaluated with non-invasive plasma sample, collected at baseline, post-neoadjuvant chemoradiation, post-surgery, and serially as disease surveillance. Bespoke mPCR-NGS assay measured the ctDNA-based MRD levels and identified a comprehensive tumor-specific genomic profile. The primary outcome is assay recurrence compared to radiologic disease recurrence, defined as radiologic confirmed disease. Exploratory endpoints are used to examine the profile of tumor. Baseline ctDNA levels were detected in 8 newly diagnosed patients. Longitudinal testing showed a decrease in ctDNA in 4 patients and residual disease in 2 patients after the start of neoadjuvant therapy. 1 patient demonstrated pCR in conjunction with ctDNA clearance. Clearance of ctDNA may correlate to a favorable pCR and indicate a lower risk of relapse, guiding the strategy for adjuvant treatment. Personalized, tumor-informed sequence alterations of the 8 patients revealed a high frequency in TP53 alterations, which occurs early during development in esophagogastric cancer. This prospective study seeks to validate the application of ctDNA surveillance and tumor molecular alterations in a larger cohort after 5 years.

Prognostic Implications of Various Surgical Procedures and Postoperative Margin Status in Gastroesophageal Junction Tumors.

Esophagogastric junction (EGJ) carcinomas often require access to two compartments of the body for good margin and lymphadenectomy. Whether it is required to do so in all patients is debatable. We analyzed outcomes of patients who underwent surgeries for EGJ carcinomas in terms of margin status and survival. This is a retrospective analysis of a prospectively maintained database of patients with EGJ adenocarcinomas operated between January 2014 and December 2016. Type of surgery performed and its impact on margin status and survival were assessed. Follow-up was for a minimum of 5 years. Ninety-four patients with EGJ carcinomas were operated on during the study period. Eight (8.51%) had involved proximal margin, and 2 of these had positive distal margin also. None had distal margin alone involved. Seventeen (18.09%) and 5 (5.32%) had a close proximal and distal margin, respectively. Radial margin was close/involved in 6 (6.38%) patients. Five-year overall survival and disease-free survival for the cohort was 38% and 30.8%, respectively. Proximal gastrectomy had a higher proximal margin positivity. Positive proximal or distal margin and a close/involved radial margin were detrimental to disease free survival and overall survival. Proximal gastrectomy is associated with a higher likelihood of proximal margin positivity. Positive margin leads to lower survival. Whether involvement of margins is just a surrogate marker of aggressive tumor or is an error in assessing extent tumor needs to be studied. Large-scale prospective studies in this regard are desirable.

Evaluation of indocyanine green tracheobronchial fluorescence (ICG-TBF) via nebulization during minimally invasive esophagectomy.

Surgical manipulation of the tracheobronchial complex is a contributing factor in pulmonary morbidity of esophagectomy. Accurate dissection between membranous trachea and bronchi with esophagus is essential. This study tests the feasibility of delivering indocyanine green (ICG) in an aerosol form to achieve tracheobronchial fluorescence (ICG-TBF). Patients with esophageal and esophagogastric junction carcinoma (N = 37) undergoing minimally invasive esophagectomy (McKeown type) were included. ICG was aerosolized by nebulization in supine position before thoracoscopy. ICG-TBF was observed with real-time fluorescence-enabled camera. Intra- and postoperative complications related to ICG were the primary focus. ICG-TBF was identified in 94.6% (35/37) of patients with median time to fluorescence identification of 15minutes (range 1-43). There were no airway injuries in the study. The ICU median stay was 2 (range 2-21) days. No intra- or postoperative complications attributable to ICG were observed. Grade 3 or 4 pulmonary complications were seen in total 8.1% patients. No 90-day postoperative mortality was seen. ICG delivered in aerosol form was found to be safe and effective in achieving ICG-TBF. It aided in accurate dissection of esophagus from the tracheobronchial complex. Further studies on effect of ICG-TBF in decreasing pulmonary complications of esophagectomy are needed.

A Novel Esophagogastrostomy Technique for Laparoscopic Proximal Gastrectomy: Conical Remnant Gastroesophageal Side-overlap Fundoplication.

There is currently no universally-accepted, ideal method of esophagogastric reconstruction to address reflux esophagitis and anastomotic complications of esophagogastrostomy after proximal gastrectomy. In June 2022, two patients with Siewert type II carcinoma of esophagogastric junction underwent laparoscopic proximal gastrectomies, using a novel esophagogastrostomy technique of Conical remnant GastroEsophageal side-Overlap fundoplication (CGEO). On postoperative day 4, upper gastrointestinal fluoroscopy was performed, with patients in downward and left oblique positions, allowing gastrografin to accumulate within fundic reconstructions. No reflux into the esophagus was subsequently observed, and both patients were discharged (postoperative days 9 and 11). Six months after surgery, endoscopic view showed that the reconstructed cardia returned to its normal state, in the absence of any reflux symptoms. As of April 2023, we have operated on four patients using CGEO, and all of them recovered without obvious reflux symptoms. CGEO is a feasible and safe reconstructive esophagogastrostomy procedure following laparoscopic proximal gastrectomy for Siewert type II esophagogastric junction carcinoma.

Proposal for T3 classification of esophagogastric junction carcinoma based on the interconnection of extramural anatomical structures.

Classification of extramural invasion of esophagogastric junction carcinoma (EGJC) is not yet established. The anatomy surrounding the EGJ alters between the mediastinum and the abdominal cavity. This review proposed a T3 classification of EGJC based on anatomical continuity. Analysis of endoscopic ultrasound images, review of intraoperative images, and detailed observation of surgical specimens were followed by a review of the literature. In the EGJ, the muscularis propria of the esophagus is enclosed in mediastinal adipose tissue called the adventitia, which is surrounded by the diaphragmatic crus and contains the paraesophageal lymph nodes (LNs). After passing through the esophageal hiatus along with the vagus nerves and blood vessels, the adventitia joins the adipose tissue containing the paracardial LNs, which is covered by the peritoneum, and then further divides into the lesser and greater omentum. The connective tissue outside the muscularis propria of the stomach, including the adipose tissue of the omentum, is called the subserosa. According to the TNM classification, T3 esophageal and gastric cancer is defined as invasion of the adventitia and subserosa, respectively. Given that the adventitia is anatomically continuous with the subserosa, T3 tumors of the EGJ can be described as those that extend through the muscularis propria but do not invade the peritoneum or diaphragmatic crus. We propose classifying T3 EGJC as "tumor extends through muscularis propria" rather than using the separate terms "adventitia" and "submucosa". T4 could be "tumor perforates serosa or invades adjacent structures", as per the current gastric cancer classification.

Safety and efficacy of tislelizumab plus chemotherapy versus chemotherapy alone as neoadjuvant treatment for patients with locally advanced gastric cancer: real-world experience with a consecutive patient cohort.

Immunotherapy plus chemotherapy has recently been applied in the neoadjuvant treatment for locally advanced gastric cancer (LAGC), while its superiority over neoadjuvant chemotherapy (NACT) alone remains to be explored. This study explored the safety and efficacy of NACT plus tislelizumab in patients with LAGC. The data on patients with LAGC who received NACT combined with radical gastrectomy and NACT plus tislelizumab followed by radical gastrectomy was retrospectively collected. Clinicopathological characteristics of the two groups were compared. A total of 119 and 50 patients with gastric cancer treated with NACT and NACT plus tislelizumab, respectively, were enrolled. No significant difference was found between the baseline data of the two groups. The operative time (210.5 ± 70.4min vs. 237.6 ± 68.4min, P=0.732), intraoperative blood loss (157.8 ± 75.9ml vs. 149.1 ± 92.5ml, P=0.609), and number of dissected lymph nodes (24.7 ± 9.3 vs. 28.1 ± 10.3, P=0.195) was not statistically different between the two groups. In comparison to the NACT plus tislelizumab group, the R0 resection rate (100% vs. 89.9%, P=0.019) and pathologic complete response rate (26.0% vs. 3.4%, P<0.001) were significantly lower in the NACT group. The postoperative complication rates were 24.4% and 26.0% in the NACT and NACT plus tislelizumab groups with no significant difference (P=0.823). In subgroup analysis, tumor regression grade (TRG) (TRG 3: 72.3% vs. 23.5%, P<0.001) and ypN stage (stages 2-3: 46.8% vs. 5.9%, P=0.003) in the NACT group were significantly higher compared with the NACT plus tislelizumab group in esophagogastric junction carcinoma. Compared with the S-1 and oxaliplatin (SOX) or 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX) NACT regimen, NACT plus tislelizumab significantly improved the efficacy and R0 resection rate of LAGC without increasing the incidence of perioperative complications, particularly in esophagogastric junction carcinoma.

Management of Esophago-Gastric Junction Carcinoma: A Narrative Multidisciplinary Review.

Esophagogastric junction (EGJ) carcinoma represents a specific site of disease, given the opportunities for multimodal clinical care and management and the possibilities of combined treatments. It encompasses various clinical subgroups of disease that are heterogeneous and deserve different treatments; therefore, the guidelines have progressively evolved over time, considering the evidence provided by clinical trials. The aim of this narrative review was to summarize the main evidence, which orientates the current guidelines, and to collect the main ongoing studies to address existing gray areas.

Long-term oncologic and surgical outcomes of robotic and laparoscopic gastrectomy for Siewert II/III esophagogastric junction carcinoma: A propensity score-matched retrospective cohort study

BackgroundThis study aimed to investigate the short-term surgical and long-term survival outcomes after robotic gastrectomy (RG) or laparoscopic gastrectomy (LG) for patients with Siewert type II and III adenocarcinoma of the esophagogastric junction (AEG). MethodsWe retrospectively analyzed 84 and 312 patients with Siewert type II/III AEG who underwent RG or LG between January 2005 and September 2016 in our center. We performed a 1:2 matched propensity score matching (PSM) analysis between the RG and LG group for clinical features to reduce confounding bias. Additionally, the long- and short-term outcomes between the RG and LG group were compared. ResultsThe clinicopathological characteristics of 246 patients (RG group: n = 82; LG group: n = 164) were well balanced after PSM. Patients in the RG group showed less estimated blood loss, less time to first flatus, less time to first ambulation, less drainage tube removed time, and retrieved more lymph nodes than the LG group. The overall complication rate was comparable between the RG and LG groups. The 5-year overall survival (OS) was 44.4% in the RG group and 43.7% in the LG group (p = 0.898). The 5-year disease-free survival (DFS) was 43.2% in the RG group and 43.2% in the LG group (p = 0.990). The RG and LG groups exhibited a similar recurrence rate and pattern within 5 years after surgery. ConclusionRobotic gastrectomy could be a feasible and safe option for patients with Siewert II/III AEG in terms of surgical and oncologic outcomes.

Molecular landscape and clinical implication of CCNE1-amplified esophagogastric cancer.

440 Background: Cyclin E1 ( CCNE1) amplification ( CCNE1Amp) drives chromosomal instability (CIN) and is associated with immune cell exclusion, liver metastasis, therapeutic resistance, and poor survival in gastric adenocarcinoma (GA). However, the clinical relevance of CCNE1Amp in a larger real-world population is unknown. Therefore, we profiled the molecular landscape of CCNE1-amplified (amp) esophagogastric cancer (EGC) and explored treatment response outcomes. Methods: Tumors were analyzed by next-generation sequencing (NGS) of DNA (592 genes, NextSeq; WES, NovaSeq) and RNA (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Deficiency in mismatch repair or microsatellite instability (dMMR/MSI-H) was tested by fragment analysis, IHC, and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (high&gt;10 mt/MB). PD-L1 was tested by IHC (22C3, 1+). Real world overall survival (OS) was extracted from insurance claims and calculated from first of treatment to last contact using Kaplan-Meier survival curves for molecularly defined cohorts. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q&lt;0.05). Results: CCNE1Amp (copy number, CN ≥6) was identified in 142/2276 (6.2%) esophageal adenocarcinoma (EA), 101/1449 (7.0%) esophagogastric junction carcinoma (EJC), 109/2607 (4.2%) GA, and 6/751 (0.8%) esophageal squamous cell carcinoma (ESCC) samples. Metastatic sites such as lymph node and liver showed higher frequency of CCNE1Amp compared to primary sites. TMB, dMMR/MSI-H, and PD-L1 expression were similar in CCNE1-amp vs non-amp tumors. CCNE1Amp was enriched in CIN type tumors (defined by increased TP53 and ERBB2 amp) and was associated with decreased mutation of CDKN2A and CDH1. In addition, CCNE1-amp tumors showed increased HER2 positivity/ ERBB2 amplification by IHC (14.3% vs 10.1%) or CN analysis (19.1% vs 10.3%). Differential gene expression analysis demonstrated increased liver X receptor/retinoid X receptor (LXR/RXR) pathway activation in tumors harboring CCNE1Amp. While there were no differences in OS between CCNE1-amp vs non-amp GA, CCNE1Amp was associated with worse OS after trastuzumab in the IHC HER2+ cohort (N=9 vs 28; HR (95% CI): 2.95 (1.18 – 7.34), p = 0.015). By contrast, there was a trend toward improved OS after immunotherapy in CCNE1-amp GA (N=9 vs 194; HR (95% CI): 0.34 (0.11 –1.07), p = 0.054). Conclusions: CCNE1Amp is associated with a distinct molecular profile in EGC and resistance to HER2-targeted therapy. While CCNE1-amp tumors are thought to be generally “immune-cold,” CCNE1-amp GA demonstrated potentially improved outcomes with immunotherapy. Further investigation of CCNE1Amp as a predictive biomarker is warranted, particularly as novel therapeutics selectively targeting CCNE1Amp are under clinical investigation.

Esophago-Gastric Junction Carcinoma: State of the Art and Ongoing Trials in a Multimodal Approach

Clinical management of Esophago-Gastric Junction (EGJ) carcinoma represents a challenge for gastrointestinal multidisciplinary tumor boards because of the opportunity of multimodal and combined treatments. The evolution of the guidelines, also in view of the classifications that have progressively helped to discriminate the various disease subsets and considering the evidence from clinical trials, can be very complex. The aim of this study is to report the main evidence on which the current guidelines are based, with a special focus on the grey areas that still exist and on ongoing studies that may provide further useful elements for the clinical management of this type of patient.

Enhancement of DNA hypomethylation alterations by gastric and bile acids promotes chromosomal instability in Barrett’s epithelial cell line

Gastric and bile acid reflux leads to chronic inflammation, resulting in methylation alterations in Barrett’s esophagus (BE) together with chromosomal instability (CIN). We investigated DNA hypomethylation following acid exposure and confirmed its significance in BE-related carcinogenesis by inducing CIN in vitro. OACP4C, an esophageal cancer cell line, and CP-A, a non-dysplastic cell line originating from BE, were exposed to acidic conditions using deoxycholic acid. CP-A exhibited substantially increased DNA hypomethylation of alpha satellite sequences in the centromere region, as well as increased levels of alpha satellite transcripts, but no changes were observed in the long interspersed nucleotide element-1 sequences distributed throughout the entire genome. These changes were not clearly found in OACP4C. Copy number changes at specific chromosomes were identified in CP-A, along with an increased number of cells exhibiting abnormal segregations, whereas these changes were rarely observed in OACP4C. The changes were maintained after several cell divisions. These findings suggest that alpha satellites are likely targets of DNA hypomethylation induced by acid exposure. CP-A was more sensitive to acid exposure than OACP4C, indicating that acid-induced DNA hypomethylation is involved in cancer development rather than progression, which could be involved in the underlying mechanism of esophagogastric junction carcinoma development.

Mapping of lymph node dissection determined by the epicenter location and tumor extension for esophagogastric junction carcinoma.

Previous studies identified the extent of lymph node dissection for esophagogastric junction (EGJ) carcinoma based on the metastatic incidence. The study aimed to determine the optimal extent and priority of lymphadenectomy based on the therapeutic efficacy from each station. The studies on the lymph node metastasis (LNM) and therapeutic efficacy index (EI) for EGJ carcinomas were identified until April 2022. The obligatory stations with the LNM rates over 5% and therapeutic EI exceeding 2% should be routinely resected for D2 dissection, whereas the optional stations with EI between 0.5% and 2% should be resected for D3 dissection in selective cases. The survey yielded 16 eligible articles including 6,350 patients with EGJ carcinoma. The metastatic rates exceeded 5% at no. 1, 2, 3, 7, 9, 11p, and 110 stations and were less than 5% in abdominal no. 4sa~6, 8a, 10, 11d, 12a, and 16a2/b1 and mediastinal no. 105~112 stations. Consequently, obligatory stations with EI over 2% were largely determined by the epicenter location and located at the upper perigastric, lower mediastinal, and suprapancreatic zones, corresponding to those with rates of LNM over 5%. Consistent with the LNM rates less than 5%, the optional stations with EI between 0.5% and 2% were largely dependent on the degree of tumor extension toward the lower perigastric, splenic hilar (grecurvature), para-aortic (less curvature of the cardia), and middle or upper mediastinal zones. The obligatory stations can be resected as an "envelope-like" wrap by transhiatal proximal gastrectomy with lower esophagectomy, whereas the optional stations for dissection are indicated by the tumor extension. The extended gastrectomy is required for the lower perigastric in the stomach-predominant tumor with gastric involvement exceeding 5.0cm, para-aortic dissection in the less curvature-predominant tumor and splenic hilar dissection in the grecurvature-predominant tumor whereas transthoracic subtotal esophagectomy is required for complete mediastinal dissection and adequate negative margin in the esophagus-predominant tumor with esophageal invasion exceeding 3.0cm.

Phase I/II trial of RVU120 (SEL120), a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors.

e15091 Background: CDK 8 /CDK19 are kinases involved in transcriptional control of embryonic development and cellular homeostasis via the mediator complex. They are also described to maintain tumor dedifferentiation and stem cell properties. A variety of cancer cells hijack the mediator complex and targeting cancer-specific gene transcription via CDK8/19 inhibition has potential for treatment of solid tumors. RVU120 (SEL120) is a selective CDK8/19 inhibitor with preclinical efficacy in hematologic malignancies and a variety of solid tumor types (Rzymski et al. 2017). RVU120 showed strong anticancer activity in preclinical triple-negative breast cancer (TNBC) models, especially in the mesenchymal stem-like (MSL) molecular subtype (Rzymski et al SABCS 2021). Methods: A Phase I/II clinical trial of RVU120 in solid tumors is currently ongoing (NCT05052255). Patients with metastatic or advanced solid tumors without available treatments receive increasing doses of RVU120 as a single oral dose every other day (QOD) for a total of 7 doses on Days 1, 3, 5, 7, 9, 11 and 13, in a 3-week treatment cycle. Primary objectives of the study are safety / tolerability of RVU120 as single agent and determination of the recommended Phase II dose (RP2D) via a 3+3 dose escalation design. Secondary objectives include objective response rate (ORR) (RECIST criteria v1.1) and PK of RVU120. Results: As of 11FEB 2022, 5 pts have been enrolled into the trial: 3 into cohort 1, 75 mg dose, 2 into cohort 2, 100 mg. None of the pts experienced a DLT, SAEs or &gt; Grade 3 AE. Treatment-related AEs were all G1 except for G2 diarrhea and weakness. Cohort 1 patients had at least 1 post-baseline tumor assessment. A 62 YO patient, stage IV esophago-gastric junction carcinoma, metastases to the liver, retroperitoneum, adrenal gland and portocaval lymph nodes, progressing after 4 lines of previous therapy, achieved a SD with a +4% change of target lesion size and progressed in cycle 6. A 65 YO patient, stage IV adenoid cystic carcinoma of the trachea, metastases to the lung and refractory to antiandrogens and radiotherapy, achieved a SD with -4% change of target lesion size after 3 cycles and is currently ongoing in cycle 5. A 43 YO pt stage IV thymic carcinoma, metastases to the lung, mediastinum, pleura and lymph nodes, progressing under cisplatin/etoposide, stopped study drug at the end of cycle 3 for PD in non-target lesions, target lesions increased by 11%. Cohort 2 patients, a 65 YO pt with pancreatic cancer stage IV, metastases to liver and lung, and a 55 YO pt with TNBC stage IV, metastases to the lung, will be evaluated end of cycle 3. Conclusions: In the first dose escalation level with single agent RVU120, no DLTs or ≥G3 AEs were observed in patients with previously progressive solid tumors. Initial assessments in 3 pts demonstrated stable disease in 2 patients. Collection of further data at higher doses is ongoing with 2 patients enrolled at 100 mg. Clinical trial information: NCT05052255.