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Introduction: Gastric cancer (GC) burden is currently evolving with regional differences associated with complex behavioural, environmental, and genetic risk factors. The LEGACy study is a Horizon 2020-funded multi-institutional research project conducted prospectively to provide comprehensive data on the tumour biological characteristics of gastroesophageal cancer from European and LATAM countries., Material and Methods: Treatment-naïve advanced gastroesophageal adenocarcinoma patients were prospectively recruited in seven European and LATAM countries. Formalin-fixed paraffin-embedded primary tumour endoscopic biopsy samples were collected and submitted for central morphological and immunohistochemical characterization and TP53 molecular assessment and Helicobacter pylori infection., Results: A total of 259 patients were included in the study: 137 (53%) from LATAM and 122 (47%) from Europe. Significant biological differences were detected between European and LATAM patients. Low representation of chromosomal instability (CIN) and HER2 positive cases were found in LATAM. MUC6 and PD-L1 were more frequently overexpressed in European cases, showing a significant correlation across the entire study population, with this association being especially pronounced in MMRdeficient cases. Both TP53 mutation by next-generation sequencing and p53 immunohistochemical aberrant pattern were linked with features associated with chromosomal instability. No regional differences were observed in H. pylori prevalence or abundance, indicating that the afore mentioned variations cannot be attributed to this factor., Conclusion: Our findings underscore a need for region-specific approaches in gastroesophageal cancer diagnosis and treatment. MUC6 emerges as a putative immune regulator that needs further investigation. Research tailored to the unique biological profiles in different global regions is crucial to effectively address the observed disparities., Competing Interests: Declarations. Conflict of interest: Dr. Alsina discloses consultancy, advisory roles, honoraria from Amgen, AstraZeneca, Beigene, Drangofly Therapeutics, Jazz Pharmaceuticals, BMS, Lilly, Novartis and MSD. Institutional research funding from Merck. FL Dr. Lordick reports institutional grants from: Astra Zeneca, Beigene, BMS, Daiichi Sankyo and Gilead, and personal fees from: Amgen, ArtTempi. Astellas, Astra Zeneca, Bayer, Biontech, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Gilead, Elsevier, Incyte, Medscape, MedUpdate, Merck Serono, MSD, PAGE, Roche, Servier, StreamedUp!, VJ Oncology, all outside the submitted work. Dr. Fleitas discloses advisory roles honoraria from Amgen, AstraZeneca, Beigene, BMS and MSD. Institutional research funding from Gilead. Speaker honoraria from Amgen, Servier, BMS, MSD, Lilly, Roche, Bayer. The other authors has no conflict of interests to declare. Ethics approval and consent to participate: The study has been conducted according to the principles of the Declaration of Helsinki (Fortaleza, Brazil, October 2013), following the Medical Research Involving Human Subjects Act and Good Clinical Practice standards. The study can be found under ClinicalTrials.gov Identifier: NCT04015466, July 11, 2019. The study protocol has been approved by the ethics committee of all patient-recruiting centers: the ethics committee of University Clinical Hospital of Valencia, Spain (reference number 2018/205), the institutional review board of VU University Medical Center Amsterdam (reference number 2019.355. NL 69480.02919), the ethics committee of Instituto de Previsión Social, Asuncion-Paraguay (reference number CA N°11–020/19), the ethical research committee of Instituto Alexander Fleming, Buenos Aires Argentina (Resolution July 25th, 2019, for LEGACy study 1 and 2 and October 3rd, 2019 for LEGACy study 3); the ethical committee of Instituto Nacional de Cancerología (INCAN, México (reference number INCAN/CEI/0486/19). The ethics committee of the University Center of Sao Joao and Medicine Faculty of Porto University, Portugal (reference 100/019), the scientific ethical Committee Pontificia University of Chili, reference 180806007, and the Drug research ethics committee of Valld’Hebron University Hospital, Barcelona, Spain with references PR (AG)387/2019 approved on October 29th, 2019 for LEGACy study 1, PR (AG)388/2019 approved in December 13th 2019 for LEGACy study 2 and PR (AG)419/2019 approved in January 30th, 2020 for Legacy study 3 respectively. All participants provided written informed consent before study enrolment. Each data-contributing partner has undergone online ethical and data training before the beginning of data collection and has managed access to the data of their center through this security system. Inside this system, a patient ID generator has generated a unique code for each participating patient to maintain data privacy., (© 2025. The Author(s).)

Shallow genome-wide cell-free DNA (cfDNA) sequencing holds great promise for non-invasive cancer monitoring by providing reliable copy number alteration (CNA) and fragmentomic profiles. Single nucleotide variations (SNVs) are, however, much harder to identify with low sequencing depth due to sequencing errors. Here we present Nanopore Rolling Circle Amplification (RCA)-enhanced Consensus Sequencing (NanoRCS), which leverages RCA and consensus calling based on genome-wide long-read nanopore sequencing to enable simultaneous multimodal tumor fraction estimation through SNVs, CNAs, and fragmentomics. Efficacy of NanoRCS is tested on 18 cancer patient samples and seven healthy controls, demonstrating its ability to reliably detect tumor fractions as low as 0.24%. In vitro experiments confirm that SNV measurements are essential for detecting tumor fractions below 3%. NanoRCS provides the opportunity for cost-effective and rapid processing, which aligns well with clinical needs, particularly in settings where quick and accurate cancer monitoring is essential for personalized treatment strategies., (Published by Cold Spring Harbor Laboratory Press.)

Purpose: The value of integrating clinical variables, radiomics, and tumor-derived cell-free DNA (cfDNA) for the prediction of survival and response to chemoradiation of patients with resectable esophageal adenocarcinoma is not yet known. Our aim was to investigate if radiomics and cfDNA metrics combined with clinical variables can improve personalized predictions., Methods and Materials: A cohort of 111 patients with resectable esophageal adenocarcinoma from 2 centers treated with neoadjuvant chemoradiation therapy was used for exploratory retrospective analyses. Models combining the clinical variables of the SOURCE survival model with radiomic features and cfDNA were built using elastic net regression and internally validated using 5-fold cross-validation. Model performance for overall survival (OS) and time to progression (TTP) were evaluated with the C-index and the area under the curve for pathologic complete response., Results: The best-performing baseline models for OS and TTP were based on the combination of SOURCE-cfDNA that reached a C-index of 0.55 and 0.59 compared with 0.44 to 0.45 with SOURCE alone. The addition of restaging positron emission tomography radiomics to SOURCE was the most promising addition for predicting OS (C-index: 0.65) and TTP (C-index: 0.60). Baseline risk stratification was achieved for OS and TTP by combining SOURCE with radiomics or cfDNA, log-rank P < .01. The best-performing combination model for the prediction of pathologic complete response reached an area under the curve of 0.61 compared with 0.47 with SOURCE variables alone., Conclusions: The addition of radiomics and cfDNA can improve the performance of an established survival model. External validity needs to be further assessed in future studies together with the optimization of radiomic pipelines., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy. Innovative treatments, like targeted therapy or immunotherapy, have recently proved to ameliorate prognosis, but a general agreement on managing oligometastatic disease has yet to be achieved. An international multi-disciplinary workshop was held in Bertinoro, Italy, in November 2022 to verify whether achieving a consensus on at least some topics was possible., Methods: A two-round Delphi process was carried out, where participants were asked to answer 32 multiple-choice questions about CT, laparoscopic staging and biomarkers, systemic treatment for different localization, role and indication of palliative care. Consensus was established with at least a 67% agreement., Results: The assembly agreed to define oligometastases as a "dynamic" disease which either regresses or remains stable in response to systemic treatment. In addition, the definition of oligometastases was restricted to the following sites: para-aortic nodal stations, liver, lung, and peritoneum, excluding bones. In detail, the following conditions should be considered as oligometastases: involvement of para-aortic stations, in particular 16a2 or 16b1; up to three technically resectable liver metastases; three unilateral or two bilateral lung metastases; peritoneal carcinomatosis with PCI ≤ 6. No consensus was achieved on how to classify positive cytology, which was considered as oligometastatic by 55% of participants only if converted to negative after chemotherapy., Conclusion: As assessed at the time of diagnosis, surgical treatment of oligometastases should aim at R0 curativity on the entire disease volume, including both the primary tumor and its metastases. Conversion surgery was defined as surgery on the residual volume of disease, which was initially not resectable for technical and/or oncological reasons but nevertheless responded to first-line treatment., (© 2024. The Author(s).)

Background: Tertiary lymphoid structures (TLSs) are thought to stimulate antitumor immunity and positively impact prognosis and response to immune checkpoint blockade. In gastric cancers (GCs), however, TLSs are predominantly found in GC with poor prognosis and limited treatment response. We, therefore, hypothesize that immune cell composition and function of TLS depends on tumor location and the tumor immune environment., Methods: Spatial transcriptomics and immunohistochemistry were used to characterize the phenotype of CD45 + immune cells inside and outside of TLS using archival resection specimens from GC primary tumors and peritoneal metastases., Results: We identified significant intrapatient and interpatient diversity of the cellular composition and maturation status of TLS in GC. Tumor location (primary vs metastatic site) accounted for the majority of differences in TLS maturity, as TLS in peritoneal metastases were predominantly immature. This was associated with higher levels of tumor-infiltrating macrophages and Tregs and less plasma cells compared with tumors with mature TLS. Furthermore, mature TLSs were characterized by overexpression of antitumor immune pathways such as B cell-related pathways, MHC class II antigen presentation while immature TLS were associated with protumor pathways, including T cell exhaustion and enhancement of DNA repair pathways in the corresponding cancer., Conclusion: The observation that GC-derived peritoneal metastases often contain immature TLS which are associated with immune suppressive regulatory tumor-infiltrating leucocytes, is in keeping with the lack of response to immune checkpoint blockade and the poor prognostic features of peritoneal metastatic GC, which needs to be taken into account when optimizing immunomodulatory strategies for metastatic GC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite the advent of neoadjuvant chemoradiotherapy (CRT), overall survival rates of esophageal adenocarcinoma (EAC) remain low. A readily induced mesenchymal transition of EAC cells contributes to resistance to CRT., Methods: In this study, we aimed to chart the heterogeneity in cell state transition after CRT and to identify its underpinnings. A panel of 12 esophageal cultures were treated with CRT and ranked by their relative epithelial-mesenchymal plasticity. RNA-sequencing was performed on 100 pre-treatment biopsies. After RNA-sequencing, Ridge regression analysis was applied to correlate gene expression to ranked plasticity, and models were developed to predict mesenchymal transitions in patients. Plasticity score predictions of the three highest significant predictive models were projected on the pre-treatment biopsies and related to clinical outcome data. Motif enrichment analysis of the genes associated with all three models was performed., Results: This study reveals NANOG as the key associated transcription factor predicting mesenchymal plasticity in EAC. Expression of NANOG in pre-treatment biopsies is highly associated with poor response to neoadjuvant chemoradiation, the occurrence of recurrences, and median overall survival difference in EAC patients (>48 months). Perturbation of NANOG reduces plasticity and resensitizes cell lines, organoid cultures, and patient-derived in vivo grafts., Conclusions: In conclusion, NANOG is a key transcription factor in mesenchymal plasticity in EAC and a promising predictive marker for outcome., (© 2024. The Author(s).)

Background: Tumors in the distal esophagus (EAC), gastro-esophageal junction including cardia (GEJAC), and stomach (GAC) develop in close proximity and show strong similarities on a molecular and cellular level. However, recent clinical data showed that the effectiveness of chemo-immunotherapy is limited to a subset of GEAC patients and that EACs and GEJACs generally benefit less from checkpoint inhibition compared to GACs. As the composition of the tumor immune microenvironment drives response to (immuno)therapy we here performed a detailed immune analysis of a large series of GEACs to facilitate the development of a more individualized immunomodulatory strategy., Methods: Extensive immunophenotyping was performed by 14-color flow cytometry in a prospective study to detail the immune composition of untreated gastro-esophageal cancers (n=104) using fresh tumor biopsies of 35 EACs, 38 GEJACs and 31 GACs. The immune cell composition of GEACs was characterized and correlated with clinicopathologic features such as tumor location, MSI and HER2 status. The spatial immune architecture of a subset of tumors (n=30) was evaluated using multiplex immunohistochemistry (mIHC) which allowed us to determine the tumor infiltration status of CD3+, CD8+, FoxP3+, CD163+ and Ki67+ cells., Results: Immunophenotyping revealed that the tumor immune microenvironment of GEACs is heterogeneous and that immune suppressive cell populations such as monocytic myeloid-derived suppressor cells (mMDSC) are more abundant in EACs compared to GACs (p<0.001). In contrast, GACs indicated a proinflammatory microenvironment with elevated frequencies of proliferating (Ki67+) CD4 Th cells (p<0.001), Ki67+ CD8 T cells (p=0.002), and CD8 effector memory-T cells (p=0.024). Differences between EACs and GACs were confirmed by mIHC analyses showing lower densities of tumor- and stroma-infiltrating Ki67+ CD8 T cells in EAC compared to GAC (both p=0.021)., Discussions: This comprehensive immune phenotype study of a large series of untreated GEACs, identified that tumors with an esophageal tumor location have more immune suppressive features compared to tumors in the gastro-esophageal junction or stomach which might explain the location-specific responses to checkpoint inhibitors in this disease. These findings provide an important rationale for stratification according to tumor location in clinical studies and the development of location-dependent immunomodulatory treatment approaches., Competing Interests: TdG has a consultant or advisory role in Mendus, GE Healthcare, and LAVA Therapeutics, is a co-founder and holds stock of LAVA Therapeutics, and received research funding from Idera Pharmaceuticals. MIH is consultant for Viatris, Johnson & Johnson, Alesi Surgical, BBraun, Stryker and Medtronic. All fees paid to institution. HL has consultant or advisory role in BMS, Lilly, MSD, Nordic Pharma, Servier and receives research funding/medication: Bayer, BMS, Celgene, Janssen, Lilly, Merck, Nordic Pharma, Philips, Roche, Servier. RP has a consulting role for Medtronic BV and MicroTech Europe; speaker fee for Pentax. TF declares institutional research funding from Genentech, Adapt immune, Roche, Beigene, Astelas, BMS, Daichii Sanyo, Amgen and speaker fees from Astrazeneca, Amgen, Bayer, BMS, Lilly, MSD and Servier. SD reports: a consultant or advisory role for BMS (related to checkpoint inhibitors); research funding, medication supply, or both from Incyte (related to checkpoint inhibitors); and speaker roles for Servier, BMS, and Benecke. SD reports: a consultant or advisory role for BMS (related to checkpoint inhibitors); research funding, medication supply, or both from Incyte (related to checkpoint inhibitors); and speaker roles for Servier, BMS, and Benecke. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Groen-van Schooten, Harrasser, Seidel, Bos, Fleitas, van Mourik, Pouw, Goedegebuure, Doeve, Sanders, Bos, van Berge Henegouwen, Thijssen, van Grieken, van Laarhoven, de Gruijl and Derks.)

Background: Rapid and complete workup of newly diagnosed esophageal cancer is vital for a timely, individual and high-quality treatment strategy. The aim of this study was to uncover potential delay, inefficiencies and non-contributing investigations in the diagnostic process in two tertiary referral centers., Methods: This retrospective cohort study included all newly diagnosed esophageal cancer patients referred to or diagnosed in the Amsterdam UMC and Karolinska University Hospital between July 2020 and July 2021. Radiology, pathological assessment and multidisciplinary team meeting reports were reviewed. To assess time interval from diagnosis to treatment, dates of diagnosis, admittance to referral hospital, MDT meeting and start of treatment were collected., Results: In total, 252 esophageal cancer patients were included, 187 were treated with curative intent. Curatively treated patients had a mean age of 66 years, were predominantly male (74.9 %) with an adenocarcinoma (71.1 %). Curatively treated patients had a median time from diagnosis to referral of seven days (IQR:0-11) and of 35 days (IQR:28-45) between diagnosis and start of treatment. Main reasons for the significant (P < 0.001) differences in time between diagnosis and treatment between centers, Amsterdam UMC (39 days) vs Karolinska (27 days), were need for additional diagnostics (47.8 %) and differences in referral routine. Gastroscopy was repeated in 32.2 % of patients, mainly for further anatomical mapping., Conclusion: Significant time differences between centers in the path from diagnosis to start treatment can be explained by differences in workup approach, referral routines and MDT meeting regulations. Repeat of gastroscopy can be prevented with clearer endoscopy guidelines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.I. van Berge Henegouwen reports a relationship with Viatris that includes: consulting or advisory. M.I. van Berge Henegouwen reports a relationship with Johnson & Johnson that includes: consulting or advisory. M.I. van Berge Henegouwen reports a relationship with Alesi Surgical that includes: consulting or advisory. M.I. van Berge Henegouwen reports a relationship with BBraun that includes: consulting or advisory. M.I. van Berge Henegouwen reports a relationship with Medtronic Inc that includes: consulting or advisory. M.I. van Berge Henegouwen reports a relationship with Stryker that includes: funding grants., (© 2023 Published by Elsevier Ltd.)

Circulating tumor DNA (ctDNA) holds promise in resectable esophageal adenocarcinoma (EAC) to predict patient outcome but is not yet sensitive enough to be clinically applicable. Our aim was to combine ctDNA mutation data with shallow whole-genome sequencing (sWGS)-derived copy number tumor fraction estimates (ichorCNA) to improve pathological response and survival prediction in EAC. In total, 111 stage II/III EAC patients with baseline (n = 111), post-neoadjuvant chemoradiotherapy (nCRT) (n = 68), and pre-surgery (n = 92) plasma samples were used for ctDNA characterization. sWGS (<5× coverage) was performed on all time-point samples, and copy number aberrations were estimated using ichorCNA. Baseline and pre-surgery samples were sequenced using a custom amplicon panel for mutation detection. Detection of baseline ctDNA was successful in 44.3% of patients by amplicon sequencing and 10.5% by ichorCNA. Combining both, ctDNA could be detected in 50.5% of patients. Baseline ctDNA positivity was related to higher T stage (cT3, 4) (p = 0.017). There was no relationship between pathological response and baseline ctDNA positivity. However, baseline ctDNA metrics (variant allele frequency > 1% or ichorCNA > 3%) were associated with a high risk of disease progression [HR = 2.23 (95% CI 1.22-4.07), p = 0.007]. The non-clearance of a baseline variant or ichorCNA > 3% in pre-surgery samples was related to early progression [HR = 4.58 (95% CI 2.22-9.46), p < 0.001]. Multi-signal analysis improves detection of ctDNA and can be used for prognostication of resectable EAC patients. Future studies should explore the potential of multi-modality sequencing for risk stratification and treatment adaptation based on ctDNA results. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

The GLOW randomized double-blind phase 3 trial 1 shows that Claudin-18.2 targeting antibody zolbetuximab combined with capecitabine and oxaliplatin improves outcome compared to placebo and chemotherapy as first-line treatment in Claudin-18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinomas., Competing Interests: Declaration of interests HWMvL reports (all payments are made to their institution) a consultant or advisory role for AstraZeneca, Beigene, BMS, and MSD (all related to checkpoint inhibitors) and for Amphera, Daiichi-Sankyo, Dragonfly, Eli Lilly, Nordic Pharma, and Servier; research funding, medication supply, or both from Incyte, Merck, Roche, and Servier (all related to checkpoint inhibitors) and from Bayer, BMS, Celgene, Janssen, Eli Lilly, Nordic Pharma, and Philips; and speaker roles for Astellas (related to checkpoint inhibitors), Benecke, Daiichi-Sankyo, JAAP, Medtalks, Novartis, and Travel Congress Management. S.D. reports a consultant or advisory role for BMS (related to checkpoint inhibitors); research funding, medication supply, or both from Incyte (related to checkpoint inhibitors); and speaker roles for Servier, BMS, and Benecke., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Vγ9Vδ2 T cells are effector cells with proven antitumor efficacy against a broad range of cancers. This study aimed to assess the antitumor activity and safety of a bispecific antibody directing Vγ9Vδ2 T cells to EGFR-expressing tumors. An EGFR-Vδ2 bispecific T-cell engager (bsTCE) was generated, and its capacity to activate Vγ9Vδ2 T cells and trigger antitumor activity was tested in multiple in vitro, in vivo, and ex vivo models. Studies to explore safety were conducted using cross-reactive surrogate engagers in nonhuman primates (NHP). We found that Vγ9Vδ2 T cells from peripheral blood and tumor specimens of patients with EGFR+ cancers had a distinct immune checkpoint expression profile characterized by low levels of PD-1, LAG-3, and TIM-3. Vγ9Vδ2 T cells could be activated by EGFR-Vδ2 bsTCEs to mediate lysis of various EGFR+ patient-derived tumor samples, and substantial tumor growth inhibition and improved survival were observed in in vivo xenograft mouse models using peripheral blood mononuclear cells (PBMC) as effector cells. EGFR-Vδ2 bsTCEs exerted preferential activity toward EGFR+ tumor cells and induced downstream activation of CD4+ and CD8+ T cells and natural killer (NK) cells without concomitant activation of suppressive regulatory T cells observed with EGFR-CD3 bsTCEs. Administration of fully cross-reactive and half-life extended surrogate engagers to NHPs did not trigger signals in the safety parameters that were assessed. Considering the effector and immune-activating properties of Vγ9Vδ2 T cells, the preclinical efficacy data and acceptable safety profile reported here provide a solid basis for testing EGFR-Vδ2 bsTCEs in patients with EGFR+ malignancies., (©2023 American Association for Cancer Research.)

Background: In trials evaluating perioperative chemotherapy for gastric cancer, which serve as the basis for treatment guidelines, patients are selected. The generalizability of these trial findings to older patients is uncertain., Methods: This population-based retrospective cohort study compared the survival outcomes of patients ≥ 75 years with gastric adenocarcinoma treated with or without neoadjuvant chemotherapy between 2015 and 2019. Additionally, the percentage of patients < 75 years and ≥ 75 years who did not proceeded to surgery after receiving neoadjuvant chemotherapy were examined., Results: A total of 1995 patients, of whom 1249 aged < 75 years and 746 aged ≥ 75 years, were included. In the group of patients ≥ 75 years, 275 patients received neoadjuvant chemotherapy and 471 patients were directly scheduled for gastrectomy. Patients ≥ 75 years treated with or without neoadjuvant chemotherapy differed significantly from one and another in characteristics. Overall survival of patients ≥ 75 years treated with or without neoadjuvant chemotherapy was not significantly different (median 34.9 vs. 32.3 months; P = 0.506), also after adjusting for potential confounders (HR 0.87; P = 0.263). Of patients ≥ 75 years who received neoadjuvant chemotherapy, 43 (15.6%) did not proceed to surgery compared to 111 (8.9%) patients < 75 years (P < 0.001)., Conclusion: Patients ≥ 75 years treated with or without chemotherapy were highly selected, and overall survival was not significantly different between both groups. Nonetheless, the proportion of patients who did not proceed to surgery following neoadjuvant chemotherapy was higher in patients ≥ 75 years compared to patients < 75 years. Therefore, neoadjuvant chemotherapy should be considered with more caution in patients ≥ 75 years, while identifying those who may benefit., (© 2023. The Author(s).)

Purpose: Definitive chemoradiotherapy (dCRT) is a treatment option with curative intent for patients with esophageal cancer that could result in late toxicities and affect health-related quality of life (HRQoL). This study aimed to review the literature and perform a meta-analysis to investigate the effect of dCRT on late toxicities and HRQoL in esophageal cancer., Methods and Materials: A systematic search was performed in MEDLINE, EMBASE, and PsychINFO. Prospective phase II and III clinical trials, population-based studies, and retrospective chart reviews investigating late toxicity or HRQoL after dCRT (≥50 Gy) were included. The HRQoL outcomes were analyzed using linear mixed-effect models with restricted cubic spline transformation. Any HRQoL changes of ≥10 points were considered clinically relevant. The risk of toxicities was calculated using the number of events and the total study population., Results: Among 41 included studies, 10 assessed HRQoL and 31 late toxicity. Global health status remained stable over time and improved after 36 months compared with baseline (mean change, +11). Several tumor-specific symptoms, including dysphagia, eating restrictions, and pain, improved after 6 months compared with baseline. Compared with baseline, dyspnea worsened after 6 months (mean change, +16 points). The risk of any late toxicity was 48% (95% CI, 33%-64%). Late toxicity risk of any grade for the esophagus was 17% (95% CI, 12%-21%), pulmonary 21% (95% CI, 11%-31%), cardiac 12% (95% CI, 6%-17%), and any other organ 24% (95% CI, 2%-45%)., Conclusions: Global health status remained stable over time, and tumor-specific symptoms improved within 6 months after dCRT compared with baseline, with the exception of dyspnea. In addition, substantial risks of late toxicity were observed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Neoadjuvant chemoradiotherapy (nCRTx) reduces the incidence of recurrence, while anastomotic leakage has shown increase the risk of recurrence. The primary objective of this retrospective study was to investigate the incidence and pattern of recurrence and secondary median recurrence-free interval and post-recurrence survival in patients with and without anastomotic leakage after multimodal therapy for esophageal adenocarcinoma., Methods: Patients with recurrence after multimodal therapy between 2010 and 2018 were included., Results: Six hundred and eighteen patients were included, 91 (14.7%) had leakage and 278 (45.0%) recurrence. Patients with leakage did not develop recurrence more often (48.4%) than those without (44.4%, [p = 0.484]). Recurrence-free interval for patients with (n = 44) and without leakage (n = 234) was 39 and 52 weeks, respectively (p = 0.049). Post-recurrence survival was 11 and 16 weeks, respectively (p = 0.702). Specified by recurrence site, post-recurrence survival for loco-regional recurrences was 27 versus 33 weeks (p = 0.387) for patients with and without leakage, for distant 9 versus 13 (p = 0.999), and for combined 11 versus 18 weeks (p = 0.492)., Conclusion and Discussion: No higher incidence of recurrent disease was observed in patients with anastomotic leakage, however it is associated with a shorter recurrence-free interval. This could have implications for surveillance, as early detection of recurrent disease could influence therapeutic options., (© 2023 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

The analysis of peripheral blood mononuclear cells (PBMCs) by flow cytometry holds promise as a platform for immune checkpoint inhibition (ICI) biomarker identification. Our aim was to characterize the systemic immune compartment in resectable esophageal adenocarcinoma patients treated with neoadjuvant ICI therapy. In total, 24 patients treated with neoadjuvant chemoradiotherapy (nCRT) and anti-PD-L1 (atezolizumab) from the PERFECT study (NCT03087864) were included and 26 patients from a previously published nCRT cohort. Blood samples were collected at baseline, on-treatment, before and after surgery. Response groups for comparison were defined as pathological complete responders (pCR) or patients with pathological residual disease (non-pCR). Based on multicolor flow cytometry of PBMCs, an immunosuppressive phenotype was observed in the non-pCR group of the PERFECT cohort, characterized by a higher percentage of regulatory T cells (Tregs), intermediate monocytes, and a lower percentage of type-2 conventional dendritic cells. A further increase in activated Tregs was observed in non-pCR patients on-treatment. These findings were not associated with a poor response in the nCRT cohort. At baseline, immunosuppressive cytokines were elevated in the non-pCR group of the PERFECT study. The suppressive subsets correlated at baseline with a Wnt/β-Catenin gene expression signature and on-treatment with epithelial-mesenchymal transition and angiogenesis signatures from tumor biopsies. After surgery monocyte activation (CD40), low CD8+Ki67+ T cell rates, and the enrichment of CD206+ monocytes were related to early recurrence. These findings highlight systemic barriers to effective ICI and the need for optimized treatment regimens., Competing Interests: MIvBH is consultant for Mylan, Johnson & Johnson, Alesi Surgical, BBraun and Medtronic, and received unrestricted research grants from Stryker. All fees paid to institution. NHM has served as a consultant for MSD, BMS, Astra Zeneca, Servier and Lilly. MFB received research funding from Celgene and Lead Pharma and has acted as a consultant for Servier. HWMvL: Consultant or advisory role: BMS, Daiichy, Dragonfly, Eli Lilly, MSD, Nordic Pharma, Servier. Research funding and/or medication supply: Bayer, BMS, Celgene, Janssen, Incyte, Eli Lilly, MSD, Nordic Pharma, Philips, Roche, Servier. Speaker role: Astellas, Daiichy, Novartis. TDdG reports to be in an advisory role for GE Healthcare, Mendus and LAVA Therapeutics, to have received a research grant from Idera Pharmaceuticals, and to be co-founder and owner of stocks of LAVA Therapeutics, outside of the submitted work. The other authors report no conflict of interest., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Competing Interests: HWMvL reports (all payments are made to their institution): a consultant or advisory role for AstraZeneca, Beigene, BMS, and MSD (all related to checkpoint inhibitors) and for Amphera, Daiichi-Sankyo, Dragonfly, Eli Lilly, Nordic Pharma, and Servier; research funding, medication supply, or both from Incyte, Merck, Roche, and Servier (all related to checkpoint inhibitors) and from Bayer, BMS, Celgene, Janssen, Eli Lilly, Nordic Pharma, and Philips; and speaker roles for Astellas (related to checkpoint inhibitors), Benecke, Daiichi-Sankyo, JAAP, Medtalks, Novartis, and Travel Congress Management. SD reports: a consultant or advisory role for BMS (related to checkpoint inhibitors); research funding, medication supply, or both from Incyte (related to checkpoint inhibitors); and speaker roles for Servier, BMS, and Benecke.

In the ASTRUM-007 randomized double-blind phase III study, Song et al. 1 showed that the combination of PD-1 inhibitors with first-line fluoropyrimidine and platinum-based chemotherapy improves outcomes in PD-L1-overexpressing esophageal squamous cell carcinomas., Competing Interests: Declaration of interests H.W.M.v.L. reports the following conflicts of interest: Consultant or advisory role: Amphera, AstraZeneca, Beigene, BMS, Daiichy-Sankyo, Dragonfly, Eli Lilly, MSD, Nordic Pharma, Servier; Research funding and/or medication supply: Bayer, BMS, Celgene, Janssen, Incyte, Eli Lilly, MSD, Nordic Pharma, Philips, Roche, Servier; Speaker role: Astellas, Benecke, Daiichy-Sankyo, JAAP, Medtalks, Novartis, Travel Congress Management B.V. S.D. reports the following conflicts of interest: Consultant or advisory role: BMS; Research funding and/or medication supply: Incyte; Speaker role: Benecke, Medtalks, Novartis, Servier., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Treatment of advanced or metastatic esophageal adenocarcinoma (EAC) follows the guidelines for gastroesophageal junction adenocarcinoma (GEJC) and gastric adenocarcinoma (GAC), but patients with EAC are often excluded from clinical studies of GEJC/GAC., Objectives: Here we describe treatment and survival of patients with advanced EAC, GEJC, and GAC to provide population-based evidence on distinctions and similarities between these populations., Design: Retrospective cohort study of patients with unresectable advanced (cT4b) or metastatic (cM1) EAC, GEJC, or GAC (2015-2020) were selected from the Netherlands Cancer Registry., Methods: Overall survival (OS) was assessed using Kaplan-Meier methods, log-rank tests, and multivariable Cox regression., Results: In all, 7391 patients were included (EAC: n  = 3346, GEJC: n  = 1246, and GAC: n  = 2798). Patients with EAC were more often males and more often had ⩾2 metastatic locations. First-line systemic therapy was received by 42%, 47%, and 36% of patients with EAC, GEJC, and GAC, respectively. Median OS was 5.0, 5.1, and 4.0 months for all patients with EAC, GEJC, and GAC, respectively ( p  < 0.001). Median OS from start of first-line therapy of patients with human epidermal growth factor receptor 2 (HER2)-negative adenocarcinomas was 7.6, 7.8, and 7.5 months ( p  = 0.12) and of patients with HER2-positive carcinoma receiving first-line trastuzumab-containing therapy was 11.0, 13.3, and 9.5 months ( p  = 0.37) in EAC, GEJC, and GAC, respectively. After multivariable adjustment, no difference in OS for patients with EAC, GEJC, and GAC was observed., Conclusion: Despite differences in clinical characteristics and treatment strategies, survival between patients with advanced EAC, GEJC, and GAC was similar. We advocate that EAC patients should not be excluded from clinical trials for patients with molecularly similar GEJC/GAC., Competing Interests: DB is an employee of BMS and holds stock in BMS and GSK. LM is an employee of, and holds stock in BMS. HvL reports grants from Roche, has served as a consultant for BMS, Celgene, Lilly, and Nordic and has received unrestricted research funding from Bayer, BMS, Celgene, Lilly, Merck Serono, MSD, Nordic, Philips, and Roche. RV reports grants from BMS and Roche. MP, PV, WD, BM, SD, and IO have no disclosures to declare., (© The Author(s), 2023.)