Esophagogastric Cancer Research Articles

Assessing the benefits of repeated esophagogastroduodenoscopy at a specialized center before gastric and esophageal cancer surgery.

The surgical treatment of gastric and esophageal cancer in Denmark is centralized in four specialized esophagogastric cancer (EGC) centers. Patients are referred after an esophagogastroduodenoscopy (EGD) at a secondary healthcare facility. The EGD is repeated at the specialized EGC center before determining a surgical treatment strategy. This multicenter retrospective study aimed to investigate the quality of EGDs performed at a secondary healthcare facility and evaluate the clinical value of repeated EGD at a specialized center when determining the surgical treatment strategy. Patients from three of the four centers, who underwent esophagectomy or gastrectomy with curative intent from 1 June 2016 to 1 May 2021, were included. EGD reports from the referral facilities and EGC centers were compared based on a predefined checklist. Furthermore, endoscopist experience, the time between examinations, and histology were registered. Finally, it was assessed whether the specialized EGD led to any substantial changes in surgical treatment. Baseline characteristics and differences in EGD reports were described and McNemar's chi-square test was performed. A logistic regression analysis was conducted to identify risk factors for a change in surgical strategy. The study included 953 patients who underwent both an initial EGD and EGD at referral to a specialized center. In 644 cases (68%), the information from the initial EGD was considered insufficient concerning preoperative tumor information. In 113 (12%) cases, the findings in the specialized EGD would lead to a significant alteration in the surgical strategy compared with the primary EGD. The findings suggest that repeated EGD at a specialized center is of clinical value and helps ensure proper surgical treatment for patients undergoing curative surgery for gastroesophageal cancer.

Technical variety of anastomotic techniques used in proximal gastrectomy with double-tract-reconstruction - a narrative review.

In the past 40 years, the incidence of esophagogastric junction cancer has been gradually increasing worldwide. Currently, surgical resection remains the main radical treatment for early gastric cancer. Due to the rise of functional preservation surgery, proximal gastrectomy has become an alternative to total gastrectomy for surgeons in Japan and South Korea. However, the methods of digestive tract reconstruction after proximal gastrectomy have not been fully unified. At present, the principal methods include esophagogastrostomy, double flap technique, jejunal interposition, and double tract reconstruction. Related studies have shown that double tract reconstruction has a good anti-reflux effect and improves postoperative nutritional prognosis, and it is expected to become a standard digestive tract reconstruction method after proximal gastrectomy. However, the optimal anastomoses mode in current double tract reconstruction is still controversial. This article aims to review the current status of double tract reconstruction and address the aforementioned issues.

Premature mortality for patients after completely resected early adenocarcinoma of the esophagus or stomach.

To establish the life expectancy burden of esophago-gastric cancer by analyzing years of life lost (YLL) for a Western patient population after treatment of early esophageal (EAC) or early gastric (GAC) adenocarcinoma. For patients with early EAC or GAC, the short-term prognosis after surgical resection is very good. Little data is available regarding long-term prognosis when compared to the general population. Two hundred and fourteen patients with pT1 EAC (n = 112) or GAC (n = 102) were included in the study. Patients with EAC underwent transthoracic en-bloc esophagectomy; those with GAC had total or subtotal gastrectomy with D2-lymphadenectomy. Surviving patients had a median follow-up of approximately 14 years. YLL was calculated using average life expectancy data from Germany. Patients with EAC were younger (median age 61 years) than those with GAC (66 years) (p = 0.031). The male:female ratio was 10:1 for EAC and 3:2 for GAC (p < 0.001). Multivariate survival analysis showed the age of the patients ≥60 years and the existence of lymph node metastasis was associated with poor prognosis. The median YLL for all patients who died over follow-up was 8.0 years. For patients under 60 years, it was approximately 20 years, and for older patients, approximately 5 years (p < 0.001) without difference in tumor stage between these age cohorts. YLL did not differ for GAC vs. EAC. After surgical resection, the prognostic burden as measured by YLL is relevant for all patients with early esophageal and gastric adenocarcinomas and especially for younger patients. Reasons for YLL need further studies.

Enhancing survival outcomes in stage Ⅲ gastric/esophagogastric junction cancer: a retrospective study of immune checkpoint inhibitors and adjuvant chemotherapy based on real-world data

Objective: To explore the efficacy of immune checkpoint inhibitors combined with adjuvant chemotherapy in patients with phase III gastric cancer and esophagogastric junction cancer. Methods: This study used a retrospective cohort study method based on real-world data. Clinical data of 403 patients with stage III gastric/esophagogastric junction cancer who underwent gastrectomy followed by adjuvant therapy in the Department of Gastric Surgery at Sun Yat-sen University Cancer Center from January 2020 to December 2023 were retrospectively collected. The study cohort comprised 147 (36.5%) patients with stage IIIA, 130 (32.3%) with stage IIIB, and 126 (31.3%) with stage IIIC gastric/esophagogastric junction cancer. Of them, 15 (3.7%) were HER-2 positive, 25 (6.2%) dMMR, and 22 (5.5%) patients Epstein-Barr virus encoding RNA (EBER) positive. Based on treatment plans, the patients were divided into immune checkpoint inhibitor combined with chemotherapy group (immune therapy group, n=110, 71 males and 39 females, median age 59 years old) and chemotherapy alone group (chemotherapy group, n=293, 186 males and 107 females, median age 60 years old). All patients in the immunotherapy group received immune checkpoint inhibitors targeting the programmed cell death protein-1 (PD-1) and its ligand (PD-L1). Of them, 85 received pembrolizumab, 10 received sintilimab, 8 received tislelizumab, 4 received camrelizumab, 2 received toripalimab, and 1 received pabocizumab. The adjuvant chemotherapy regimens used among the chemotherapy alone group includes SOX regimen (132 cases), XELOX (102 cases), S-1 monotherapy (44 cases), and other regimens (15 cases). The 3-year DFS rate of the two groups was compared, and subgroup analysis was conducted based on different ages, molecular phenotypes, pTNM staging, extranodal infiltration, and tumor length. Results: The median follow-up was 20.5 months (range 3.1~46.3), with a 3-year overall DFS rate of 61.4% for the entire 403 patients. The 3-year DFS rate for the immunotherapy group was 82.7%, higher than the chemotherapy alone group (58.8%), with a statistically significant difference (P=0.021). Multivariate analysis showed that postoperative immunotherapy was a protective factor for DFS (HR=0.352, 95%CI: 0.180~0.685). Subgroup analysis showed that stage IIIC (HR=0.416, 95%CI: 0.184~0.940), aged ≥60 years (HR=0.336, 95%CI: 0.121~0.934) and extranodal invasion (HR=0.378, 95%CI: 0.170~0.839) were associated with benefit from the combined immune adjuvant chemotherapy, while no association was observed for MMR, HER-2 or EBER status. Conclusion: Stage III gastric/esophagogastric junction cancer patients may benefite from postoperative immune checkpoint inhibitor combined with adjuvant chemotherapy in real-world settings.

European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4)

IntroductionThe OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD). MethodsGuidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD. ResultsModerate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended. DiscussionThese multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment.

Systemic inflammation score as a predictor of death within one year after esophagectomy.

After radical resection for esophageal cancer, death within 1year of surgery can occur due both to recurrence and to other diseases, even after postoperative complications have been overcome. This study identified risk factors for early death within 1year of esophagectomy for reasons other than death in hospital in patients undergoing esophagectomy for esophageal cancer or esophagogastric junction cancer. We reviewed 366 patients who underwent esophagectomy without adjuvant treatment between January 2009 and July 2022 for thoracic esophageal cancer or esophagogastric junction cancer. Patients who died within 1year excluding in-hospital death were compared with those who did not. Multivariable logistic regression analysis was used to identify predictors of death within 1year after surgery. Death within 1year occurred in 32 of 366 patients, 24 from primary disease and 8 from other diseases. Deaths within 1year were significantly older than the other cases, had significantly lower % vital capacity (%VC), and occurred significantly more often in cases in advanced stages of disease. In a multivariable analysis, a systemic inflammation score (SIS) based on serum albumin level and lymphocyte-to-monocyte ratio was identified as an independent predictor of death within 1year. As SIS increased, %VC decreased significantly, and CRP level and neutrophil-lymphocyte ratio increased significantly. There was no relationship between SIS and pN. Death within 1year increased as SIS increased (p = 0.001 for trend). SIS assessment undertaken before beginning esophageal cancer treatment is a useful predictor of death within 1year of surgery.

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

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

Treatment and Rehabilitation for Esophageal Cancer—Striving to Meet Obstacles and Long-term Impacts

Background Following esophagogastric cancer treatment, patients with esophageal cancer and their relatives struggle with adjusting to a new everyday life as they experience various challenges after treatment requiring rehabilitation. Health professionals must address long-term impacts on patients’ health, everyday life, family functioning, and support needs. Objective This qualitative descriptive study aimed to explore patients’, relatives’, and health professionals’ experience with long-term impacts and rehabilitation after treatment for esophageal cancer. Methods A qualitative approach based on a phenomenological-hermeneutical methodology was used. Two methods were selected in the study: focus group interviews with health professionals and individual interviews with patients and relatives. Inductive thematic analysis with inspiration from Braun and Clarke was used for data analysis. Results Three main themes emerged from the data analysis: (1) forced into limitations in everyday life, (2) learning and navigating a new everyday life, and (3) rehabilitation accepting new normality. Conclusion Patients and relatives experience persistent long-term impacts after treatment for esophageal cancer, making rehabilitation strenuous and demanding. Relatives take considerable responsibility for the patients’ rehabilitation but feel invisible and unsupported by health professionals. Health professionals acknowledge the severity of long-term impacts but fail to prepare patients and relatives for the impacts and do not see the relatives’ need for support. Implications for Practice The study emphasizes the need for a proactive approach in the healthcare system, addressing patients’ and relatives’ physical and psychological vulnerability. Cancer nurses need to prepare and involve patients and relatives in treatment, long-term impacts, and rehabilitation.

Top advances of the year: Gastroesophageal cancer.

The advancement of minimally invasive surgery, a clearer definition of the role of radiation therapy, and the incorporation of immunotherapy have changed the management of esophagogastric cancers. Novel agents targeting new pathways continue to move forward.

Risk Factors for Long-term Body Weight Loss After Proximal Gastrectomy: A Retrospective Analysis.

Proximal gastrectomy (PG) is a therapy for early-stage proximal gastric cancer and offers advantages such as the preservation of food storage capacity and less body weight loss (BWL). Nevertheless, significant BWL following PG may occur, affecting the patient's well-being and survival. In this study, we aimed to identify the relevant factors for BWL following PG by analyzing an institutional database of patients. We enrolled 58 consecutive patients who underwent PG for gastric or esophagogastric junction cancer at our institution between April 2004 and March 2021. Based on BWL at 12 months postoperatively, we retrospectively compared and examined patient characteristics, surgical details, and nutritional markers. The mean BWL of the 58 patients included in this analysis was 14.0±7.2%. When the patients were divided into BWL-moderate (n=29) and BWL-severe (n=29) groups using a cutoff value of 15.7%, the latter experienced early BWL within 1 month postoperatively, primarily due to body fat mass reduction, with no recovery during the 60 months of follow up. In contrast, gradual recovery was observed among patients in the BWL-moderate group after experiencing the lowest body weight 24 months postoperatively. A greater decrease in body fat mass than in muscle mass was observed in both groups. Blood hemoglobin levels did not recover in the BWL-severe group. The BWL-severe group after proximal gastrectomy demonstrated significantly greater early postoperative BWL, primarily attributed to a reduction in body fat mass, with hardly any recovery. Early postoperative nutritional intervention might be proposed to prevent long-term BWL.

Predictors of textbook outcome following oesophagogastric cancer surgery.

Textbook outcome (TO) is a composite measure representing an ideal perioperative course, which has been utilized to assess the quality of care in oesophagogastric cancer (OGC) surgery. We aim to determine TO rates among OGC patients in a UK tertiary center, investigate predictors of TO attainment, and evaluate the relationship between TO and survival. A retrospective analysis of a prospectively collected departmental database between 2006 and 2021 was conducted. Patients that underwent radical OGC surgery with curative intent were included. TO attainment required margin-negative resection, adequate lymphadenectomy, uncomplicated postoperative course, and no hospital readmission. Predictors of TO were investigated using multivariable logistic regression. The association between TO and survival was evaluated using Kaplan-Meier analysis and Cox regression modeling. In sum, 667 esophageal cancer and 312 gastric cancer patients were included. TO was achieved in 35.1% of esophagectomy patients and 51.3% of gastrectomy patients. Several factors were independently associated with a low likelihood of TO attainment: T3 stage (odds ratio (OR): 0.41, 95% confidence interval (CI) [0.22-0.79], p = 0.008) and T4 stage (OR:0.26, 95% CI [0.08-0.72], p = 0.013) in the esophagectomy cohort and high BMI (OR:0.93, 95% CI [0.88-0.98], p = 0.011) in the gastrectomy cohort. TO attainment was associated with greater overall survival and recurrence-free survival in esophagectomy and gastrectomy cohorts. TO is a relevant quality metric that can be utilized to compare surgical performance between centers and investigate patients at risk of TO failure. Enhancement of preoperative care measures can improve TO rates and, subsequently, long-term survival.

Abstract 3890: Comprehensive molecular and immunological characterization of early-onset esophagogastric cancer

Abstract Background: The incidence of early-onset esophagogastric cancer (EOEGC), defined as age of diagnosis &amp;lt;50, has increased in recent decades. Compared to average-onset esophagogastric cancer (AOEGC), EOEGC are more likely to be genomically stable, have diffuse histology, and present with more advanced disease. Here, we utilized a large real-world data cohort to characterize EOEGC with molecular and immune signatures. Methods: 5,175 esophagogastric cancer (EGC) samples (&amp;lt;50 yrs, n=530; ≥50 yrs, n=4645) were tested by next generation sequencing (NGS) (592, NextSeq; WES, NovaSeq) and whole transcriptome sequencing (WTS) (NovaSeq) (Caris Life Sciences, Phoenix, AZ). EGC patients with age &amp;lt;50 and ≥50 were classified as EOEGC and AOEGC, respectively. Deficient mismatch repair (dMMR)/microsatellite-instability (MSI) was tested by IHC and NGS. Tumor mutational burden (TMB) totaled somatic mutations per tumor (high&amp;gt;10 mt/MB). Pathway enrichment determined by Gene Set Enrichment Analysis (Broad Institute, Cambridge, MA). Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q &amp;lt; 0.05). Results: EOEGC had higher frequency of CDH1 (18.9% vs 6.5%) but lower frequency of TP53 (65.9% vs 74.4%) mutations compared to AOEGC (all q&amp;lt;0.05). EOEGC had higher frequency of CCNE1 (6.8% vs 4.4%), MYC (6.1% vs 4.1%) and FGFR2 (3.45% vs 1.87%) copy number alterations and ARHGAP26 (5.67% vs 2.2%) fusion. EOEGC had lower frequency of TMB high (3.8 vs 10.1%) and dMMR/MSI-H (1.3% vs 5.7%) (all p&amp;lt;0.05). EOEGC had pathway enrichment of epithelial mesenchymal transition (EMT) (NES: 1.8, FDR: 0.0) and angiogenesis (NES: 1.3, FDR: 0.24). EOEGC had lower median MAPK pathway activity score (MPAS) (-0.16 vs 0.13, p&amp;lt;0.05). Analysis of inferred immune cell infiltrates showed that EOEGC had increased infiltration of B cells (4.7% vs 3.9%) and M2 macrophages (3.6% vs 3%) but decreased infiltration of M1 macrophages (3.7% vs 4%) (all q&amp;lt;0.05). EOEGC had increased T cell inflamed signature (31.3% vs 26.1%, p&amp;lt;0.05) and increased expression of HAVCR2 (TIM3) but decreased expression of FOXP3 and CD274 (PD-L1) (FC: 0.84-1.09, all p&amp;lt;0.05). There was no difference in LAG3, CTLA4, and IDO1 gene expression. Conclusion: EOEGC has several unique molecular and tumor immune microenvironment features. In this real world cohort, EOEGC has increased frequency of CDH1 mutations, ARHGAP26 fusions, enrichment of EMT and angiogenesis pathways, decreased MAPK pathway activity, decreased frequency of TMB high and dMMR/MSI-H, and a unique immune cell infiltrate with decreased M1 macrophages and increased M2 macrophages. These unique differential characteristics present therapeutic opportunities but also demonstrate the limitations of currently approved therapies in this subset of patients. Citation Format: Lawrence W. Wu, Sachin K. Deshmukh, Sharon Wu, Joanne Xiu, Alex Farrell, Vincent Lam, Emil Lou, Sanjay Goel, Chadi Nabhan, Ryan H. Moy. Comprehensive molecular and immunological characterization of early-onset esophagogastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3890.

Abstract 1757: Pan-cancer analysis identifies signatures of HRD-positivity in germline BRCA1/2 mutated non-BRCA associated cancers

Abstract Introduction: BRCA-associated cancers (breast, ovarian, pancreas, and prostate) with germline pathogenic mutations in BRCA1/2 (gBRCA1/2) are associated with homologous recombination deficiency (HRD) and benefit from platinum/PARPi. However, the role of gBRCA1/2 in non-BRCA assoc. cancers is poorly understood. HRD tumors present with ‘genomic scars’ that can be quantified in tumor profiling (“HRD-sum” score). We reasoned that the HRD-sum score together with germline mutation status (including loss of wild-type) is a strong correlate of HRD-positivity. Leveraging 42,448 prospectively sequenced patients across 63 cancer types, we sought to characterize the prevalence of the HRD-positivity in non-BRCA-assoc. cancers. Methods: Allele-specific copy number data was inferred using FACETS. HRD-sum was calculated as a sum of the numbers of telomeric imbalances, large-scale transitions and genome-wide losses of heterozygosity. Calculating each score was iteratively optimized to improve detection of the scars using MSK-IMPACT targeted sequencing data using patient-matched WES data from 1841 tumors as reference. Germline mutations were identified by a clinically validated pipeline and annotated for pathogenicity using ClinVar. After excluding low quality tumors, 27,375 patients were retained for analysis. “HRD-positive” tumors are those with gBRCA1/2 mutations, loss of wild type, and an HRD-sum score &amp;gt;=42. Results: Expectedly, gBRCA1/2 mutations were more frequent in BRCA-assoc. cancers (7.2%, 558 of 7,737 patients) compared to non-BRCA-assoc. cancers (2.6%, 500 of 19,638) (p=5e-60). Among non-BRCA-assoc. cancers, gBRCA1/2 were most common in esophagogastric (3.9%), lung (3%), hepatobiliary (2.9%), and bladder (2.8%) cancers. Although biallelic loss in gBRCA1/2 patients was sig. higher in BRCA-assoc. cancers (80% vs. 37% in non-BRCA-assoc.), several cancer types showed high rates of loss of wild-type including gBRCA1 tumors in hepatobiliary (5/5) and endometrial (10/11) cancers. HRD-sum scores in all gBRCA1/2 biallelic tumors were sig. higher (median 58) compared to monoallelic (26) or wild-type (25) tumors. Notably, the non-BRCA assoc. cancers with biallelic gBRCA1/2 harbored higher HRD-sum scores compared to monoallelic (median 51 vs. 22, p&amp;lt;0.0001). These include cancer types such as endometrial (64 vs. 37, p= 0.0014) and esophagogastric (62 vs. 45, p=0.0017). In all, 68% of gBRCA1/2 patients in BRCA-assoc. cancers showed HRD-positivity. Interestingly, 18% (91/500) of gBRCA1/2 patients in non-BRCA-assoc. cancers also showed HRD-positivity. These included 52% of esophagogastric, 28% of lung, and 22% of bladder cancer patients with gBRCA1/2. Conclusion: Using a robust measure to detect HRD scars from MSK-IMPACT panel data, we demonstrate evidence for BRCA-mediated tumorigenesis in an expanded spectrum of cancers with potential therapeutic relevance. Citation Format: Daniel M. Muldoon, Miika Mehine, Samuel Tischfield, A. Rose Brannon, Marc Ladanyi, Zsofia K. Stadler, David B. Solit, Alexander Drilon, Michael F. Berger, Yonina Murciano-Goroff, Chaitanya Bandlamudi. Pan-cancer analysis identifies signatures of HRD-positivity in germline BRCA1/2 mutated non-BRCA associated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1757.

Abstract 911: Automatic identification of subjective appetite or weight loss in clinician notes empowers studies of cachexia

Abstract Cachexia is a debilitating syndrome characterized by loss of skeletal muscle tissue that affects over 50% of cancer patients. Defining cachexia for the purposes of epidemiologic analyses has historically been determined by specific weight loss over specific time, and more recently relied on technically challenging interpretation of imaging studies. Subjective appetite or weight loss (AWL) as documented from clinician notes may offer another method of defining a similar phenotype. Although annotation of free-text notes at scale is challenging, we hypothesized that natural language processing (NLP) might successfully annotate AWL from cancer diagnosis medical notes and that such annotations would follow patterns expected from classic cachexia studies. We created a gold-standard dataset for NLP training and validation by manually labeling AWL in a cohort of 762 free-text initial consultation notes that were extracted from lung and pancreatic adenocarcinoma electronic health records. Using these labels, we fine-tuned a pre-trained neural Longformer model to classify whether a patient has symptoms of cachexia. The AWL model was evaluated on a cohort of 391 pan-cancer notes independent of the training cohort and achieved an AUC of 0.92, precision of 0.88, recall of 0.95, and accuracy of 0.94. To test whether the labels generated by this model behaved as expected from classic cachexia studies, we applied the model to 46,980 initial consultation notes from a pan-cancer cohort of patients with tumor genomic profiling from MSK-IMPACT, an FDA-authorized tumor sequencing assay. Overall, AWL was present in 28% of the patients and it was associated with gastrointestinal cancers, which is expected from previous studies of cachexia. Our analysis revealed that esophagogastric and pancreatic cancer patients had the highest rates of cachexia at around 67%. We also observed that patients with cachexia symptoms have a reduced overall survival compared to patients without (HR=1.80, 95% CI=[1.75, 1.85]), which held in several specific cancers including NSCLC (HR=1.79, 95% CI=[1.66, 1.94]), pancreatic cancer (HR=1.34, 95% CI=[1.22, 1.47]), and colorectal cancer (HR=1.71, 95% CI=[1.55, 1.89]). Cachexia symptoms were more prevalent in male patients than in female patients. Underweight patients by BMI at presentation were most likely to have cachexia symptoms. These results reciprocate well-established information about cancer cachexia, demonstrating that our text classification NLP model can be reliably used to predict AWL from free-text medical notes. AWL may thus be a viable means of studying correlates of cachexia at scale in real-world cohorts. Citation Format: Tricia Park, Karl Pichotta, Christopher J. Fong, Nikolaus Schultz, Puneeth Iyengar, Justin Jee, Ed Reznik. Automatic identification of subjective appetite or weight loss in clinician notes empowers studies of cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 911.

Abstract 2704: cGAS-STING drives myeloid inflammation in chromosomally unstable esophageal cancer

Abstract Esophageal adenocarcinoma (EAC) is an aggressive disease characterized by chromosomal instability (CIN), whereby cells continuously acquire chromosomal abnormalities that promote therapeutic resistance, immune evasion and metastasis. CIN in cancers also fuels the misplacement of genomic DNA in the form of structural abnormalities of the nucleus, such as micronuclei (MN), that lead to chronic activation of the cytosolic DNA sensing cGAS-STING pathway. However, how chronic cGAS-STING pathway activation is tolerated and shapes the tumor landscape of CINhigh EAC cancers is poorly understood. Using publicly available RNA-seq and genome sequencing data of EAC tumours and esophageal cancer cell lines as well as a panel of EAC cell lines, we demonstrate that the core cGAS-STING pathway machinery is rarely inactivated in EAC despite high levels of baseline CIN and aneuploidy. Through transcriptomic profiling of an isogenic EAC precursor cell line model of variable CIN and cGASKO/WT EAC cell lines we show that both chronic and transient CIN-driven cGAS-STING activation converge on the expression of CXCR1/2 ligands and other pro-inflammatory cytokines and chemokines rather than typical anti-tumor type I interferon signalling in EAC cells. Indeed, a novel transcriptional signature of cGAS+ micronuclear burden-correlated genes correlates with orthogonal measures of CIN in EAC tumours and esophagogastric cancer cell lines and is associated with an enrichment in myeloid-derived cells as well as poor prognosis. Correspondingly, using multiplexed immunofluorescence (IF) we find that a high preponderance of cGAS+MN and STING expression in human EAC samples is associated with decreased tumor purity, increased myeloid cell and macrophage infiltration, and increased peripheral blood neutrophil counts, indicative of tumor-promoting myeloid inflammation. Ongoing multiplexed IF and single-nuclei RNAseq analysis of cGAS+MNhigh and cGAS+MNlow EAC tumors will further help characterise the components that comprise the CIN EAC tumor microenvironment (TME) and the CIN- and cGAS-STING-dependent cell-cell interactions that govern it. Taken together, our findings provide an explanation for the observed maintenance of cGAS and STING in EAC and identify disruption of cGAS-STING-dependent myeloid cell inflammation and recruitment as a potential therapeutic target for CINhigh EAC. Citation Format: Bruno Beernaert, Erkin Erdal, Rose Clark, Tong Liu, Ester M. Hammond, Eileen E. Parkes. cGAS-STING drives myeloid inflammation in chromosomally unstable esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2704.

Effectiveness of Preoperative Immunonutrition in Improving Surgical Outcomes after Radical Cystectomy for Bladder Cancer: Study Protocol for a Multicentre, Open-Label, Randomised Trial (INu-RC).

Radical cystectomy (RC) with pelvic lymph node dissection is the standard treatment for patients with limited-stage muscle-invasive bladder cancer. RC is associated with a complication rate of approximately 50-88%. Immunonutrition (IMN) refers to the administration of substrates, such as omega-3 fatty acids, arginine, glutamine, and nucleotides, that modulate the immune response. IMN has been associated with improved outcomes following surgery for esophagogastric, colorectal and pancreatic cancer. In this paper, we describe a study protocol for a multicentre, randomised, open-label clinical trial to evaluate the effect of IMN in patients undergoing RC for bladder cancer. A 7-day preoperative course of IMN is compared with a standard high-calorie high-protein oral nutritional supplement. The primary outcome of this study is the rate of complications (infectious, wound-related, gastrointestinal, and urinary complications) in the first 30 days after RC. Secondary outcomes include time to recovery of bowel function and postoperative mobilisation, changes in muscle strength and body weight, biochemical modifications, need for blood transfusion, length of stay, readmission rate, and mortality. The results of this study may provide new insights into the impact of IMN on postoperative outcomes after RC and may help improve IMN prescribing based on patient nutritional status parameters.

Staging laparoscopy in gastric cancer patients: From a Dutch nationwide Delphi consensus towards a standardized protocol

BackgroundStaging laparoscopy is a common diagnostic tool in gastric cancer, but its performance varies widely. The aim of this study was to gain Dutch nationwide consensus regarding the indications for and execution of staging laparoscopy in patients with gastric cancer. MethodsAll surgeons in the Netherlands specialized in gastric cancer surgery (n = 52) were asked to participate in a Delphi consensus study. The study involved an initial questionnaire with a 3-point Likert scale, an online consensus meeting, and a second questionnaire using a 2-point Likert scale (agree/disagree). Consensus was defined as 70% or more agreement among participants. ResultsIn total, 45 experts completed both questionnaires (87% response rate). Consensus was reached on the indication to perform staging laparoscopy in cT3-4 or cN + or diffuse-type gastric cancer, including Siewert type III oesophagogastric junctional cancer. The experts agreed that if preoperative scans suggest infiltration of surrounding organs (cT4), the tumour's resectability should explicitly be investigated. Consensus was also reached for a systematic peritoneal cavity inspection according to Sugarbaker's Peritoneal Cancer Index (PCI) score. All regions should be inspected routinely, although the omental bursa may be inspected on indication. Aspiration of ascites or peritoneal washing should be performed for cytology. The experts agreed that restaging laparoscopy should be performed before resection in case of progressive disease on preoperative imaging. Without progression, global inspection was considered sufficient. ConclusionsThe results of this Dutch nationwide Delphi consensus study exposed the variability of performing staging laparoscopy in patients with gastric cancer and provided the concept for a standardized protocol.

O101: Current guidelines on physical activity do not prevent skeletal muscle loss and physical decline prior to Oesophagogastric cancer surgery: a new benchmark for prehabilitation?

Abstract Prehabilitation is being widely adopted to optimise physical health prior to surgery. However, there remains a lack of consensus regarding exercise type and intensity with current guidance extrapolated from generic, non-cancer populations. The WHO and American College of Sports Medicine (ACSM) recommend 600-1200 Metabolic Equivalent minutes (MET-mins) per week of physical activity (PA) but the effectiveness of this recommendation in cancer populations is unknown. Patients undergoing treatment for Oesophagogastric cancer were prospectively recruited. International Physical Activity Questionnaire (IPAQ) quantified PA at baseline and throughout treatment. Two cohorts were defined (lowPA and highPA) based on ACSM cut-off of 1200 MET-mins/week. Outcome measures were physical function (1 minute sit-to-stand, 1mSTS), CT muscle mass, chemotoxicity, and failure to complete planned treatment. 38 patients completed all study assessments (highPA n=20, lowPA n=18) with no difference in baseline characteristics or disease stage between groups. LowPA group showed declines in 1mSTS performance following chemotherapy, whereas the highPA group improved (mean difference -4 versus +10, p=0.001). Whilst both saw a decline in skeletal muscle mass, the lowPA group lost significantly more (mean difference -5.1 versus -1.8, p=0.007). There were trends towards a lower incidence of severe chemotoxicity (30% vs 61%, p=0.054) and failure to complete planned treatment (15% versus 28%, p=.33) in the highPA group. Whilst further research is required to define the most effective prehabilitation strategy, this study is the first to suggest a new benchmark to preserve muscle mass and function is higher than current guidelines and should be considered when developing prehabilitation recommendations.

O113: Predictors of textbook outcome following oesophagogastric cancer surgery

Abstract Textbook outcome (TO) is a multidimensional composite measure representing an ideal perioperative course, which has been utilised to assess the quality of care in oesophagogastric cancer surgery. We aim to determine TO rates among oesophagogastric cancer patients in a UK tertiary centre, investigate predictors of TO attainment, and evaluate the relationship between TO and survival. A retrospective analysis of a prospectively collected departmental database between 2006-2021 was conducted. Patients that underwent radical oesophagogastric cancer surgery with curative intent were included. TO attainment required margin-negative resection, adequate lymphadenectomy, uncomplicated postoperative course, and no hospital readmission. Predictors of TO were investigated using multivariable logistic regression. The association between TO and survival was evaluated using Kaplan-Meier analysis and Cox regression modelling. 667 oesophageal cancer and 312 gastric cancer patients were included. TO was achieved in 35.1% of oesophagectomy patients and 51.3% of gastrectomy patients. Several factors were independently associated with a low likelihood of TO attainment: T3 stage (OR:0.41, 95% CI [0.22-0.79], p=0.008) and T4 stage (OR:0.26, 95% CI [0.08-0.72], p=0.013) in the oesophagectomy cohort and high BMI (OR:0.93, 95% CI [0.88-0.98], p=0.011) in the gastrectomy cohort. TO attainment was associated with greater overall survival in oesophagectomy and gastrectomy cohorts, however, it was not associated with recurrence-free survival in the gastrectomy cohort. TO is a useful multidimensional quality improvement metric that can be utilised to compare surgical quality between centres and investigate patients at risk of TO failure. Implementation of preoperative care measures can improve rates of TO and long-term survival.

O214: The tumour immune microenvironment and its response to exercise during treatment for Oesophagogastric cancer

Abstract Introduction Pre-clinical studies suggest that exercise during cancer treatment may enhance tumour regression and promote an anti-tumorigenic immune microenvironment. Considering the evolution of immunotherapy in oesophagogastric cancer, further understanding of the host-tumour immune response to exercise therapy is of significant interest. Methods Using multiplex immunofluorescence, resection specimens of 30 patients with oesophageal adenocarcinoma were labelled for CD3, CD4, CD8, PD-1, PD-L1, FOXP3, CD68, and PanCK to characterise tumour and peri-tumoral immune infiltrate. All patients received the same neoadjuvant chemotherapy prior to oesophagectomy. 14 patients who engaged with a structured prehabilitation exercise program (mixed aerobic and resistance training twice-weekly) were case-matched with 16 control patients who did not. Results The prehabilitation group had a significant increase (per mm2 ) in cytotoxic T-cells (99.4 vs 13.8, p=0.003). There was also a significant increase in immune suppressive macrophages, exhausted T-helper and cytotoxic T-cells. The only significant change in the peritumoural sections was an increase in exhausted CD8 cytotoxic-T cells in the prehabilitation group (3.3 vs 1.4, p=0.043). There was no difference in the number of Treg or T-helper cells within, or around the tumour sections. Conclusions This study is the ‘first-in-man’ to show that exercise prehabilitation during chemotherapy impacts on the tumour immune microenvironment in patients with oesophageal adenocarcinoma. Exercise results in an increased abundance of both anti-tumorigenic and immunosuppressive cell types. These finding warrant further investigation, especially in the context of modern immunotherapy treatments, to understand the clinical impact that exercise oncology has on tumour regression.