The tumor immune composition of mismatch repair deficient and Epstein-Barr virus-positive gastric cancer: A systematic review.

BACKGROUND: Gastric cancer (GC), known for its unfavorable prognosis, has been classified in four distinct molecular subtypes. These subtypes not only exhibit differences in their genome and transcriptome but also in the composition of their tumor immune microenvironment. The microsatellite instable (MSI) and Epstein-Barr virus (EBV) positive GC subtypes show clear clinical benefits from immune checkpoint blockade, likely due to a neoantigen-driven and virus-driven antitumor immune response and high expression of immune checkpoint molecule PD-L1. However, even within these subtypes response to checkpoint inhibition is variable, which is potentially related to heterogeneity in the tumor immune microenvironment (TIME) and expression of co-inhibitory molecules. We conducted a systematic review to outline the current knowledge about the immunological features on the TIME of MSI and EBV + GCs. METHODS: A systematic search was performed in PubMed, EMBASE and Cochrane Library. All articles from the year 1990 and onwards addressing immune features of gastric adenocarcinoma were reviewed and included based on predefined in- and exclusion criteria. RESULTS: In total 5962 records were screened, of which 139 were included that reported immunological data on molecular GC subtypes. MSI and EBV + GCs were reported to have a more inflamed TIME compared to non-MSI and EBV- GC subtypes. Compared to microsatellite stable (MSS) tumors, MSI tumors were characterized by higher numbers of CD8 + and FoxP3 + T cells, and tumor infiltrating pro- and anti-inflammatory macrophages. HLA-deficiency was most common in MSI tumors compared to other molecular GC subtypes and associated with lower T and B cell infiltrates compared to HLA-proficient tumors. EBV + was associated with a high number of CD8 + T cells, Tregs, NK cells and macrophages. Expression of PD-L1, CTLA-4, Granzyme A and B, Perforin and interferon-gamma was enriched in EBV + tumors. Overall, MSI tumors harbored a more heterogeneous TIME in terms of immune cell composition and immune checkpoints compared to the EBV + tumors. DISCUSSION AND CONCLUSION: MSI and EBV + GCs are highly Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration.; 2019pro-inflammatory immune cell populations. Although studies on the direct comparison of EBV + and MSI tumors are limited, EBV + tumors show less intra-subgroup heterogeneity compared to MSI tumors. More studies are needed to identify how Intra-subgroup heterogeneity impacts response to immunotherapy efficacy.

Diagnostic workup for esophageal cancer patients can be improved with checklists and clearer protocols; a comparative study between two tertiary centers in Europe.

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.

Patterns of recurrent disease after neoadjuvant chemoradiotherapy and esophageal cancer surgery with curative intent in a tertiary referral center.

BACKGROUND: Recurrence is frequently observed after esophageal cancer surgery, with dismal post-recurrence survival. Neoadjuvant chemoradiotherapy followed by esophagectomy is the gold standard for resectable esophageal tumors in the Netherlands. This study investigated the recurrence patterns and survival after multimodal therapy. METHODS: This retrospective cohort study included patients with recurrent disease after neoadjuvant chemoradiotherapy followed by esophagectomy for an esophageal adenocarcinoma in the Amsterdam UMC between 01 and 01-2010 and 31-12-2018. Post-recurrence treatment and survival of patients were investigated and grouped by recurrence site (loco-regional, distant, or combined loco-regional and distant). RESULTS: In total, 278 of 618 patients (45.0%) developed recurrent disease after a median of 49 weeks. Thirty-one patients had loco-regional (11.2%), 145 distant (52.2%), and 101 combined loco-regional and distant recurrences (36.3%). Post-recurrence survival was superior for patients with loco-regional recurrences (33 weeks, 95%CI 7.3-58.7) compared to distant (12 weeks, 95%CI 6.9-17.1) or combined loco-regional and distant recurrent disease (18 weeks, 95%CI 9.3-26.7). Patients with loco-regional recurrences treated with curative intent had the longest survival (87 weeks, 95%CI 6.9-167.4). CONCLUSION: Recurrent disease after potentially curative treatment for esophageal cancer was most frequently located distantly, with dismal prognosis. A subgroup of patients with loco-regional recurrence was treated with curative intent and had prolonged survival. These patients may benefit from intensive surveillance protocols, and more research is needed to identify these patients.

The meaning of screening: detection of brain metastasis in the adjuvant setting for stage III melanoma.

BACKGROUND: The incidence of melanoma is increasing and 37% of patients with metastatic melanoma eventually have brain metastasis (BM). Currently, there is no consensus on screening for BM in patients with resected stage III melanoma. However, given the high incidence of BM, routine screening magnetic resonance imaging (MRI) of the brain is considered in patients with completely resected stage III melanoma before the start of adjuvant treatment. The aim of this study was to assess the yield of screening for BM in these patients. MATERIALS AND METHODS: A single-center cohort study was carried out in the Erasmus MC, Rotterdam, The Netherlands, a large tertiary referral center for patients with melanoma. Eligible patients with complete resection of stage III melanoma and a screening MRI of the brain, made within 12 weeks after resection and before adjuvant treatment (programmed cell death protein 1 inhibitors, dabrafenib-trametinib), available between 1 August 2018 and 1 January 2021, were included. RESULTS: A total of 202 patients were included. Eighteen (8.9%) of 202 patients had extracranial metastasis at screening. Two (1.1%) of the remaining 184 patients had BM at screening, resulting in a switch from adjuvant treatment to ipilimumab-nivolumab. At a median follow-up of 21.2 months, BM was detected in another 4 (2.4%) of 166 patients who started with adjuvant treatment. CONCLUSIONS: The yield of screening MRI of the brain is low after complete resection of stage III melanoma, before the start of adjuvant treatment. Therefore, routine screening MRI is not recommended in this setting.

Pre-treatment tumor-infiltrating T cells influence response to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a disease with dismal treatment outcomes. Response to neoadjuvant chemoradiation (CRT) varies greatly. Although the underlying mechanisms of CRT resistance are not identified, accumulating evidence indicates an important role for local antitumor immunity. To explore the immune microenvironment in relation to response to CRT we performed an in-depth analysis using multiplex immunohistochemistry, flow cytometry and mRNA expression analysis (NanoString) to generate a detailed map of the immunological landscape of pretreatment biopsies as well as peripheral blood mononuclear cells (PBMCs) of EAC patients. Response to CRT was assessed by Mandard's tumor regression grade (TRG), disease-free- and overall survival. Tumors with a complete pathological response (TRG 1) to neoadjuvant CRT had significantly higher tumor-infiltrating T cell levels compared to all other response groups (TRG 2-5). These T cells were also in closer proximity to tumor cells in complete responders compared to other response groups. Notably, immune profiles of near-complete responders (TRG 2) showed more resemblance to non-responders (TRG 3-5) than to complete responders. A high CD8:CD163 ratio in the tumor was associated with an improved disease-free survival. Gene expression analyses revealed that T cells in non-responders were Th2-skewed, while complete responders were enriched in cytotoxic immune cells. Finally, complete responders were enriched in circulating memory T cells. preexisting immune activation enhances the chance for a complete pathological response to neoadjuvant CRT. This information can potentially be used for future patient selection, but also fuels the development of immunomodulatory strategies to enhance CRT efficacy.

Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas.

BACKGROUND: Gastroesophageal adenocarcinomas (GEAs) are heterogeneous cancers where immune checkpoint inhibitors have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr virus (EBV)-positive subtypes. Immune checkpoint inhibitor responses are markedly lower in diffuse/genome stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies. PATIENTS AND METHODS: Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (N = 453 GEAs) and archival GEA resection specimen (N = 71). The Cancer Genome Atlas RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristics within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses. RESULTS: Our results confirmed substantial heterogeneity in the tumor microenvironment between distinct subtypes. While MSI-high and EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+ T cells, macrophages and B cells and, in ∼50% of cases, evidence for tertiary lymphoid structures. In contrast, CIN cancers possessed CD8+ T cells predominantly at the invasive margin while tumor-associated macrophages showed tumor infiltrating capacity. Relatively T cell-rich 'hot' CIN GEAs were often from Western patients, while immunological 'cold' CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1. CONCLUSIONS: These results reveal the diversity of immune phenotypes of GEA. Half of GS gastric cancers have tertiary lymphoid structures and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities.

MSI as a predictive factor for treatment outcome of gastroesophageal adenocarcinoma.

Gastroesophageal cancers are a major cause of death worldwide and treatment outcomes remain poor. Adequate predictive biomarkers have not been identified. Microsatellite instability (MSI) as a result of mismatch repair deficiency is present in four to twenty percent of gastroesophageal cancers and has been associated with favorable survival outcomes compared to microsatellite stable tumors. This prognostic advantage may be related to immunosurveillance, which may also explain the favorable response to immune checkpoint inhibition observed in MSI high (MSI-H) tumors. The value of conventional cytotoxic treatment in MSI-H tumors is unclear and results on its efficacy range from detrimental to beneficial effects. Here the recent data on MSI as a predictive factor for outcome of gastroesophageal cancer treatment is reviewed.

Down syndrome associated with hypothyroidism and chronic pericardial effusion: echocardiographic follow-up.

We present a 39-year-old male patient with Down syndrome who was evaluated for fatigue, palpitations and bouts of cyanosis. Physical examination showed features of trisomy-21(Down syndrome), with a slow pulse rate, distant cardiac sounds and absent apex beat. He had normal jugular venous pressure without pulsus paradoxus. The ECG showed QRS microvoltage and flattened P and T segments. The 48-hour ambulatory ECG depicted normal sinus rhythm with intermittent short PR interval without tachyarrhythmias. The chest Xray revealed cardiomegaly without pulmonary venous congestion. Although serial transthoracic echocardiographic examination demonstrated pericardial effusion with features of tamponade, there were no overt signs of clinical cardiac tamponade. Biochemically, the serum thyroxine of 3 pmol/l (normal 10 to 25) and thyroid-stimulating hormone of 160 mU/l (normal 0.20 to 4.20)) were compatible with hypothyroidism. The patient was treated with L-thyroxine sodium daily, which was gradually increased to 0.125 mg daily. Within a few months he lost weight and became more alert; furthermore, the symptoms of hypothyroidism and the pericardial effusion resolved. It can be concluded that Down syndrome may be associated with hypothyroidism and pericardial effusion. These were alleviated following hormone replacement. Regular evaluation of thyroid function tests is important in Down syndrome. (Neth Heart J 2007;15:67-70.).