Phenotypic immune characterization of gastric and esophageal adenocarcinomas reveals profound immune suppression in esophageal tumor locations.

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.

Impact of 18FFDG-PET/CT and Laparoscopy in Staging of Locally Advanced Gastric Cancer: A Cost Analysis in the Prospective Multicenter PLASTIC-Study.

BACKGROUND: Unnecessary D2-gastrectomy and associated costs can be prevented after detecting non-curable gastric cancer, but impact of staging on treatment costs is unclear. This study determined the cost impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FFDG-PET/CT) and staging laparoscopy (SL) in gastric cancer staging. MATERIALS AND METHODS: In this cost analysis, four staging strategies were modeled in a decision tree: (1) 18FFDG-PET/CT first, then SL, (2) SL only, (3) 18FFDG-PET/CT only, and (4) neither SL nor 18FFDG-PET/CT. Costs were assessed on the basis of the prospective PLASTIC-study, which evaluated adding 18FFDG-PET/CT and SL to staging advanced gastric cancer (cT3-4 and/or cN+) in 18 Dutch hospitals. The Dutch Healthcare Authority provided 18FFDG-PET/CT unit costs. SL unit costs were calculated bottom-up. Gastrectomy-associated costs were collected with hospital claim data until 30 days postoperatively. Uncertainty was assessed in a probabilistic sensitivity analysis (1000 iterations). RESULTS: 18FFDG-PET/CT costs were €1104 including biopsy/cytology. Bottom-up calculations totaled €1537 per SL. D2-gastrectomy costs were €19,308. Total costs per patient were €18,137 for strategy 1, €17,079 for strategy 2, and €19,805 for strategy 3. If all patients undergo gastrectomy, total costs were €18,959 per patient (strategy 4). Performing SL only reduced costs by €1880 per patient. Adding 18FFDG-PET/CT to SL increased costs by €1058 per patient; IQR €870-1253 in the sensitivity analysis. CONCLUSIONS: For advanced gastric cancer, performing SL resulted in substantial cost savings by reducing unnecessary gastrectomies. In contrast, routine 18FFDG-PET/CT increased costs without substantially reducing unnecessary gastrectomies, and is not recommended due to limited impact with major costs. TRIAL REGISTRATION: NCT03208621. This trial was registered prospectively on 30-06-2017.

Gastric and duodenal cancer in individuals with Lynch syndrome: a nationwide cohort study.

Background: Lynch syndrome increases the risk of gastric cancer (GC) and duodenal cancer (DC), particularly in individuals with MLH1 and MSH2 pathogenic variants (PVs). To provide further insight into whether, and from what age, esophagogastroduodenoscopy (EGD) surveillance may be beneficial, we evaluated the cumulative incidence and tumour characteristics of GC and DC in a large nationwide cohort of Dutch individuals with LS. Methods: For this retrospective nationwide cohort study, clinical data of individuals with LS registered at the Dutch Hereditary Cancer Registry were matched with pathology reports filed by the Dutch Pathology registry. All individuals registered between Jan 1, 1989 and Dec 31, 2021 with proven or putative PVs in one of the mismatch repair genes were included. Cumulative incidences of GC and DC were estimated for high-risk (MLH1, MSH2 and EpCAM) and low-risk (MSH6 and PMS2) PVs using competing risk methodology (Fine and Gray method) with death due to other causes as competing risk. Findings: Among 1002 individuals with high-risk and 765 individuals with low-risk PVs, 29 GCs (1.6%) and 39 DCs (2.2%) were diagnosed. Cumulative incidence of GC and DC under the age of 50 was very low (≤1%) for all individuals. At age 70 and 75, cumulative incidence of GC was 3% [95% CI 1%-5%] and 5% [3%-8%] for high-risk PVs and 1% [0%-2%] and 1% [0%-2%] for low-risk PVs (p = 0.006). For DC, cumulative incidence at age 70 and 75 was 5% [3%-7%] and 6% [3%-8%] in high-risk, 1% [0%-1%] and 2% [0%-4%] in low-risk PVs, respectively (p = 0.01). Primary tumour resection was performed in 62% (18/29) of GCs and 77% (30/39) of DC cases. Early-stage GC, defined as TNM stage I, was found in 32% (9/28) of GCs. Early-stage DC, defined as TNM stage I-IIa, was found in 39% (14/36) of DCs. Interpretation: Individuals with MLH1, MSH2, and EpCAM PVs have an increased risk of developing GC and DC at the age of 70 years, but this risk is very low before the age of 50 years. The age of onset of surveillance, the yield of GC and DC during EGD surveillance, and its cost-effectiveness should be subject of future studies. Funding: None.

The impact of sex on treatment and outcome in relation to histological subtype in patients with resectable gastric cancer: Results from the randomized CRITICS trial.

BACKGROUND AND OBJECTIVE: This study aims to investigate the impact of sex on outcome measures stratified by histological subtype in patients with resectable gastric cancer (GC). METHODS: A post-hoc analysis of the CRITICS-trial, in which patients with resectable GC were treated with perioperative therapy, was performed. Histopathological characteristics and survival were evaluated for males and females stratified for histological subtype (intestinal/diffuse). Additionally, therapy-related toxicity and compliance were compared. RESULTS: Data from 781 patients (523 males) were available for analyses. Female sex was associated with a distal tumor localization in intestinal (p = 0.014) and diffuse tumors (p < 0.001), and younger age in diffuse GC (p = 0.035). In diffuse GC, tumor-positive resection margins were also more common in females than males (21% vs. 10%; p = 0.020), specifically at the duodenal margin. During preoperative chemotherapy, severe toxicity occurred in 327 (63%) males and 184 (71%) females (p = 0.015). Notwithstanding this, relative dose intensities were not significantly different between sexes. CONCLUSIONS: Positive distal margin rates were higher in females with diffuse GC, predominantly at the duodenal site. Females also experience more toxicity, but this neither impacts dose intensities nor surgical resection rates. Clinicians should be aware of these different surgical outcomes when treating males and females with GC.

Patients' perspectives and the perceptions of healthcare providers in the treatment of early rectal cancer; a qualitative study.

BACKGROUND: Shared decision-making has become of increased importance in choosing the most suitable treatment strategy for early rectal cancer, however, clinical decision-making is still primarily based on physicians' perspectives. Balancing quality of life and oncological outcomes is difficult, and guidance on patients' involvement in this subject in early rectal cancer is limited. Therefore, this study aimed to explore preferences and priorities of patients as well as physicians' perspectives in treatment for early rectal cancer. METHODS: In this qualitative study, semi-structured interviews were performed with early rectal cancer patients (n = 10) and healthcare providers (n = 10). Participants were asked which factors influenced their preferences and how important these factors were. Thematic analyses were performed. In addition, participants were asked to rank the discussed factors according to importance to gain additional insights. RESULTS: Patients addressed the following relevant factors: the risk of an ostomy, risk of poor bowel function and treatment related complications. Healthcare providers emphasized oncological outcomes as tumour recurrence, risk of an ostomy and poor bowel function. Patients perceived absolute risks of adverse outcome to be lower than healthcare providers and were quite willing undergo organ preservation to achieve a better prospect of quality of life. CONCLUSION: Patients' preferences in treatment of early rectal cancer vary between patients and frequently differ from assumptions of preferences by healthcare providers. To optimize future shared decision-making, healthcare providers should be aware of these differences and should invite patients to explore and address their priorities more explicitly during consultation. Factors deemed important by both physicians and patients should be expressed during consultation to decide on a tailored treatment strategy.

Spatial immune composition of tumor microenvironment in patients with pancreatic cancer.

This study examined the composition of the immune microenvironment at different sites within resected pancreas specimens from patients with pancreatic ductal adenocarcinoma (PDAC). Therefore, single-cell suspensions were made from fresh tumor and non-tumorous tissue. Fourteen patients were included from whom twelve PDAC and five non-tumorous samples were obtained. These samples were analyzed with a nineteen marker panel on the Aurora spectral flow cytometer. Furthermore, slides from formalin-fixed paraffine PDACs of eight additional patients were stained with eight markers and analyzed by multispectral imaging. These corresponded to central tumor, periphery of the tumor, i.e., invasive front and resected lymph node and were divided into tumor and adjacent tissue. In the single-cell suspension, a decreased ratio between lymphoid and myeloid cells and between M1 and M2 macrophages was observed in the tumor tissue compared to non-tumorous tissue. Furthermore, an increase in CD169 + macrophages in patients undergoing neoadjuvant therapy was found. Using immunofluorescence, more macrophages compared to T cells were observed, as well as a lower ratio of CD8 to M2 macrophage, a higher ratio of CD4-CD8 T cells and a higher ratio of immune-suppressive cells to pro-inflammatory cells in the PDAC area compared to the adjacent non-tumorous tissue. Finally, there were more immune-suppressive cells in the central tumor area compared to the invasive front. In conclusion, we show a gradient in the immune-suppressive environment in PDAC from most suppressive in the central tumor to least suppressive in distant non-tumorous tissue.

The impact of the COVID-19 pandemic on the diagnosis, stage, and treatment of esophagogastric cancer.

BACKGROUND: The COVID-19 pandemic has affected the entire global healthcare system, including oncological care. This study investigated the effects of the COVID-19 pandemic on the diagnosis, stage, and treatment of esophagogastric cancer in the Netherlands. METHODS: Patients diagnosed in 2020 were divided into 5 periods, based on the severity of the COVID-19 pandemic in the Netherlands, and compared to patients diagnosed in the same period in the years 2017-2019. Patient characteristics and treatments were evaluated for esophageal cancer (EC) and gastric cancer (GC) separately. RESULTS: The number of esophagogastric cancer diagnoses decreased prominently during the first 2 months of the COVID-19 pandemic. During this period, a significantly higher percentage of GC patients was diagnosed with incurable disease (52.5% in 2017-2019 and 67.7% in 2020, p = 0.011). We observed a significant reduction in the percentage of patients with potentially curable EC treated with resection and neoadjuvant chemoradiotherapy (from 35.0% in 2017-2019 to 27.3% in 2020, p < 0.001). Also, patients diagnosed with incurable GC were treated less frequently with a resection (from 4.6% in 2017-2019 to 1.5% in 2020, p = 0.009) in the second half of 2020. CONCLUSIONS: Compared to previous years, the number of esophagogastric cancer diagnoses decreased in the first 2 months of the COVID-19 pandemic, while an increased percentage of patients was diagnosed with incurable disease. Both in the curative and palliative setting, patients were less likely to be treated with a surgical resection.

Longitudinal immune monitoring of patients with resectable esophageal adenocarcinoma treated with Neoadjuvant PD-L1 checkpoint inhibition.

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/ß-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.

Prognostic Value of T-Cell Density in the Tumor Center and Outer Margins in Gastric Cancer.

Tumor-infiltrating lymphocytes are associated with the survival of gastric cancer patients. T-cell densities in the tumor and its periphery were previously identified as prognostic T-cell markers for resectable gastric cancer. Immunohistochemistry for 5 T-cell markers, CD3, CD45RO, CD8, FOXP3, and granzyme B was performed on serial sections of N = 251 surgical resection specimens of patients treated with surgery only in the D1/D2 trial. Positive T cells were digitally quantified into tiles of 0.25 mm2 across 3 regions: the tumor center (TC), the inner invasive margin, and the outer invasive margin (OIM). A classification and regression tree model was employed to identify the optimal combination of median T-cell densities per region with cancer-specific survival (CSS) as the outcome. All statistical tests were 2-sided. CD8OIM was identified as the most dominant prognostic factor, followed by FOXP3TC, resulting in a decision tree containing 3 prognostically distinct subgroups with high (Hi) or low (Lo) density of the markers: CD8OIMHi, CD8OIMLo/FOXP3TCHi, and CD8OIMLo/FOXP3TCLo. In a multivariable Cox regression analysis, which included pathological T and N stages, Lauren histologic types, EBV status, microsatellite instability, and type of surgery, the immune subgroups were independent predictors for CSS. CSS was lower for CD8OIMLo/FOXP3TCHi (HR: 5.02; 95% CI: 2.03-12.42) and for CD8OIMLo/FOXP3TCLo (HR: 7.99; 95% CI: 3.22-19.86), compared with CD8OIMHi (P < .0001). The location and density of both CD8+ and FOXP3+ T cells in resectable gastric cancer are independently associated with survival. The combination of CD8OIM and FOXP3TC T-cell densities is a promising stratification factor that should be validated in independent studies.

Clinical consequences of diagnostic variability in the histopathological evaluation of early rectal cancer.

INTRODUCTION: In early rectal cancer, organ sparing treatment strategies such as local excision have gained popularity. The necessity of radical surgery is based on the histopathological evaluation of the local excision specimen. This study aimed to describe diagnostic variability between pathologists, and its impact on treatment allocation in patients with locally excised early rectal cancer. MATERIALS AND METHODS: Patients with locally excised pT1-2 rectal cancer were included in this prospective cohort study. Both quantitative measures and histopathological risk factors (i.e. poor differentiation, deep submucosal invasion, and lymphatic- or venous invasion) were evaluated. Interobserver variability was reported by both percentages and Fleiss' Kappa- (ĸ) or intra-class correlation coefficients. RESULTS: A total of 126 patients were included. Ninety-four percent of the original histopathological reports contained all required parameters. In 73 of the 126 (57.9%) patients, at least one discordant parameter was observed, which regarded histopathological risk factors for lymph node metastases in 36 patients (28.6%). Interobserver agreement among different variables varied between 74% and 95% or ĸ 0.530-0.962. The assessment of lymphovascular invasion showed discordances in 26% (ĸ = 0.530, 95% CI 0.375-0.684) of the cases. In fourteen (11%) patients, discordances led to a change in treatment strategy. CONCLUSION: This study demonstrated that there is substantial interobserver variability between pathologists, especially in the assessment of lymphovascular invasion. Pathologists play a key role in treatment allocation after local excision of early rectal cancer, therefore interobserver variability needs to be reduced to decrease the number of patients that are over- or undertreated.

Molecular characterization of gastric adenocarcinoma diagnosed in patients previously treated for Hodgkin lymphoma or testicular cancer.

INTRODUCTION: The risk of developing gastric cancer is increased in patients treated with radiotherapy for Hodgkin lymphoma (HL) or testicular cancer (TC). This study aims to assess if gastric adenocarcinoma after treatment for HL/TC (t-GC) is molecularly different from gastric adenocarcinoma in the general population. METHODS: Patients were diagnosed with t-GC ≥5 years after treatment for HL/TC. Four molecular subtypes were identified using immunohistochemical and molecular analyses: Epstein-Barr virus (EBV), mismatch repair (MMR) deficiency or microsatellite instability (MSI), aberrant p53 staining as surrogate for chromosomal instability (sCIN), and a surrogate for genomic stability (sGS) without these aberrations. Results were compared with gastric cancer in the general population (p-GC) described in literature. RESULTS: Molecular subtyping of 90 t-GCs resulted in 3% EBV, 8% MSI, 36% sCIN and 53% sGS. 3/6 of MSI t-GCs had MLH1 promoter methylation and 2/6 were explained by double somatic mutations in MMR genes. T-GCs were more frequently sGS than p-GCs (53% vs. 38%, p = 0.04). T-GC was more frequently sGS in HL/TC patients diagnosed before 1990, than after 1990 (63% vs. 38%, p = 0.03). T-GCs located in the antrum, an area that receives high irradiation doses, were more frequently sGS (61% vs. 28% in p-GCs, p = 0.02). CONCLUSION: Our results demonstrate that t-GCs are more frequently of the sGS subtype than p-GCs. An association of t-GC of the sGS subtype with prior anticancer treatment is suggested by the high frequency in HL/TC patients who were treated before 1990, a time period in which HL/TC treatments were more extensive.

Microsatellite instability and sex differences in resectable gastric cancer - A pooled analysis of three European cohorts.

OBJECTIVE: Biological sex differences in cancer are increasingly acknowledged. Here, we examined these differences in clinicopathological characteristics and survival in microsatellite instability (MSI)-high and microsatellite stable (MSS) gastric cancer (GC). DESIGN: We analysed MSI status by polymerase chain reaction (PCR) and/or mismatch repair (MMR) status by immunohistochemistry in a pooled analysis of individual patient data from one retrospective cohort from Cologne, and the randomised phase III clinical trials D1/D2 and CRITICS. All patients had resectable adenocarcinoma of the stomach and/or gastro-oesophageal junction. Patients were treated with either surgery only or perioperative chemo(radio)therapy. RESULTS: MSI and/or MMR analyses on 1307 tumours resulted in 1192 (91.2%) MSS and/or MMR proficient (MMRP) [median age, 65 years; 759 males (63.7%); 619 treated with surgery only (51.9%)], and 115 (8.8%) MSI-high [median age, 69 years; 67 males (58.3%); 76 treated with surgery only (66.1%)] GC cases. Males had shorter overall survival (OS) than female MSI-high GC (5-year OS 34.7% vs. 69.7%; hazard ratio (HR) 2.68, 95%CI 1.60 to 4.49; p < 0.001). Females with MSI-high had longer OS than those with MSS/MMRP GC (HR 0.61, 95%CI 0.41 to 0.92; p = 0.02). Males with MSI-high did not have longer OS than those with MSS/MMRP GC (HR 1.26, 95%CI 0.94 to 1.69; p = 0.12). CONCLUSIONS: MSI-high GC males had a significantly worse prognosis compared to their female counterparts in three independent cohorts. In addition, the favourable prognostic value of MSI was only seen in females and not in males. These observations emphasise the need to consider sex differences in prognosis and treatment effects in oncology. CLINICAL TRIAL REGISTRATION: The CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02.

Triplet Chemotherapy with Cisplatin versus Oxaliplatin in the CRITICS Trial: Treatment Compliance, Toxicity, Outcomes and Quality of Life in Patients with Resectable Gastric Cancer.

(1) Background: Perioperative chemotherapy is the current standard treatment for patients with resectable gastric cancer. Based on studies in patients with metastatic gastric cancer, oxaliplatin has replaced cisplatin in the curative setting as well. However, evidence to prefer oxaliplatin over cisplatin in the curative setting is limited. (2) Methods: We compared patient-related and tumor-related outcomes for cisplatin versus oxaliplatin in patients with resectable gastric cancer treated with perioperative chemotherapy in the CRITICS trial. (3) Results: Preoperatively, 632 patients received cisplatin and 149 patients received oxaliplatin. Preoperative severe toxicity was encountered in 422 (67%) patients who received cisplatin versus 89 (60%) patients who received oxaliplatin (p = 0.105). Severe neuropathy was observed in 5 (1%) versus 6 (4%; p = 0.009) patients, respectively. Postoperative severe toxicity occurred in 109 (60%) versus 26 (51%) (p = 0.266) patients; severe neuropathy in 2 (1%) versus 2 (4%; p = 0.209) for patients who received cisplatin or oxaliplatin, respectively. Diarrhea impacted the quality of life more frequently in patients who received oxaliplatin compared to cisplatin. Complete or near-complete pathological response was achieved in 94 (21%) versus 16 (15%; p = 0.126) patients who received cisplatin or oxaliplatin, respectively. Overall survival was not significantly different in both groups (p = 0.300). (4) Conclusions: Both cisplatin and oxaliplatin are legitimate options as part of systemic treatment in patients with resectable gastric cancer.

Predictive value of chromosome 18q11.2-q12.1 loss for benefit from bevacizumab in metastatic colorectal cancer: A post hoc analysis of the randomized phase III-trial AGITG-MAX.

The VEGF-A monoclonal antibody bevacizumab is currently recommended for first-line treatment of all metastatic colorectal cancer (mCRC) patients. Cost-benefit ratio and side-effects however necessitate patient selection. A large retrospective yet nonrandomized study showed that patients with loss of chromosome 18q11.2-q12.1 in the tumor and treated with bevacizumab have 3 months improved median progression-free (PFS) and overall survival (OS) benefit compared to patients without this loss and/or treatment modality. Implementation for loss of chromosome 18q11.2-q12.1 as a marker in clinical practice mandates evidence in a randomized controlled trial for bevacizumab. Of the trials with randomization of chemotherapy vs chemotherapy with bevacizumab, the AGITG-MAX trial was the only one with tumor materials available. Chromosome 18q11.2-q12.1 copy number status was measured for 256 AGITG-MAX trial patients and correlated with PFS according to a predefined analysis plan with marker-treatment interaction as the primary end-point. Chromosome 18q11.2-q12.1 losses were detected in 71% of patients (181/256) characteristic for mCRC. Consistent with the nonrandomized study, significant PFS benefit of bevacizumab was observed in patients with chromosome 18q11.2-q12.1 loss (P = .009), and not in patients without 18q loss (P = .67). Although significance for marker-treatment interaction was not reached (Pinteraction  = .28), hazard ratio and 95% confidence interval of this randomized cohort (HRinteraction  = 0.72; 95% CI = 0.39-1.32) shows striking overlap with the nonrandomized study cohorts (HRinteraction  = 0.41; 95% CI = 0.32-0.8) supported by a nonsignificant Cochrane χ2 test (P = .11) for heterogeneity. We conclude that post hoc analysis of the AGITG-MAX RCT provides supportive evidence for chromosome 18q11.2-q12.1 as a predictive marker for bevacizumab in mCRC patients.

Quality of Life Is Associated With Survival in Patients With Gastric Cancer: Results From the Randomized CRITICS Trial.

BACKGROUND: The evaluation of health-related quality of life (HRQoL) in clinical trials has become increasingly important because it addresses the impact of treatment from the patient's perspective. The primary aim of this study was to investigate the effect of postoperative chemotherapy and chemoradiotherapy (CRT) after neoadjuvant chemotherapy and surgery with extended (D2) lymphadenectomy on HRQoL in the CRITICS trial. Second, we investigated the potential prognostic value of pretreatment HRQoL on event-free survival (EFS) and overall survival (OS). PATIENTS AND METHODS: Patients in the CRITICS trial were asked to complete HRQoL questionnaires (EORTC Quality-of-Life Questionnaire-Core 30 and Quality-of-Life Questionnaire gastric cancer-specific module) at baseline, after preoperative chemotherapy, after surgery, after postoperative chemotherapy or CRT, and at 12 months follow-up. Patients with at least 1 evaluable questionnaire (645 of 788 randomized patients) were included in the HRQoL analyses. The predefined endpoints included dysphagia, pain, physical functioning, fatigue, and Quality-of-Life Questionnaire-Core 30 summary score. Linear mixed modeling was used to assess differences over time and at each time point. Associations of baseline HRQoL with EFS and OS were investigated using multivariate Cox proportional hazards analyses. RESULTS: At completion of postoperative chemo(radio)therapy, the chemotherapy group had significantly better physical functioning (P=.02; Cohen's effect size = 0.42) and less dysphagia (P=.01; Cohen's effect size = 0.38) compared with the CRT group. At baseline, worse social functioning (hazard ratio [HR], 2.20; 95% CI, 1.36-3.55; P=.001), nausea (HR, 1.89; 95% CI, 1.39-2.56; P<.001), worse WHO performance status (HR, 1.55; 95% CI, 1.13-2.13; P=.007), and histologic subtype (diffuse vs intestinal: HR, 1.94; 95% CI, 1.42-2.67; P<.001; mixed vs intestinal: HR, 2.35; 95% CI, 1.35-4.12; P=.003) were significantly associated with worse EFS and OS. CONCLUSIONS: In the CRITICS trial, the chemotherapy group had significantly better physical functioning and less dysphagia after postoperative treatment. HRQoL scales at baseline were significantly associated with EFS and OS.

Response to neoadjuvant chemotherapy and survival in molecular subtypes of resectable gastric cancer: a post hoc analysis of the D1/D2 and CRITICS trials.

BACKGROUND: Epstein-Barr virus positivity (EBV+) and microsatellite instability (MSI-high) are positive prognostic factors for survival in resectable gastric cancer (GC). However, benefit of perioperative treatment in patients with MSI-high tumors remains topic of discussion. Here, we present the clinicopathological outcomes of patients with EBV+, MSI-high, and EBV-/MSS GCs who received either surgery only or perioperative treatment. METHODS: EBV and MSI status were determined on tumor samples collected from 447 patients treated with surgery only in the D1/D2 trial, and from 451 patients treated perioperatively in the CRITICS trial. Results were correlated to histopathological response, morphological tumor characteristics, and survival. RESULTS: In the D1/D2 trial, 5-year cancer-related survival was 65.2% in 47 patients with EBV+, 56.7% in 47 patients with MSI-high, and 47.6% in 353 patients with EBV-/MSS tumors. In the CRITICS trial, 5-year cancer-related survival was 69.8% in 25 patients with EBV+, 51.7% in 27 patients with MSI-high, and 38.6% in 402 patients with EBV-/MSS tumors. Interestingly, all three MSI-high tumors with moderate to complete histopathological response (3/27, 11.1%) had substantial mucinous differentiation. No EBV+ tumors had a mucinous phenotype. 115/402 (28.6%) of EBV-/MSS tumors had moderate to complete histopathological response, of which 23/115 (20.0%) had a mucinous phenotype. CONCLUSIONS: In resectable GC, MSI-high had favorable outcome compared to EBV-/MSS, both in patients treated with surgery only, and in those treated with perioperative chemo(radio)therapy. Substantial histopathological response was restricted to mucinous MSI-high tumors. The mucinous phenotype might be a relevant parameter in future clinical trials for MSI-high patients.

Prognostic value of tumor markers and ctDNA in patients with resectable gastric cancer receiving perioperative treatment: results from the CRITICS trial.

AIM: To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer. METHODS: We performed a post hoc analysis of the CRITICS trial, in which 788 patients received perioperative therapy. Association between survival and pretreatment CEA, CA 19-9, alkaline phosphatase, neutrophils, hemoglobin and lactate dehydrogenase were explored in uni- and multivariable Cox regression analyses. Likelihoods to receive potentially curative surgery were investigated for patients without elevated tumor markers versus one of the tumor markers elevated versus both tumor markers elevated. The association between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 patients with available ctDNA data. RESULTS: In multivariable analysis, in which we corrected for allocated treatment and other baseline characteristics, elevated pretreatment CEA (HR 1.43; 95% CI 1.11-1.85, p < 0.001) and CA 19-9 (HR 1.79; 95% CI 1.42-2.25, p < 0.001) were associated with worse OS. Likelihoods to receive potentially curative surgery were 86%, 77% and 60% for patients without elevated tumor marker versus either elevated CEA or CA 19-9 versus both elevated, respectively (p < 0.001). Although both preoperative presence of ctDNA and tumor markers were prognostic for survival, no association was found between these two parameters. CONCLUSION: CEA and CA 19-9 were independent prognostic factors for survival in a large cohort of European patients with resectable gastric cancer. No relationship was found between tumor markers and ctDNA. These factors could potentially guide treatment choices and should be included in future trials to determine their definitive position. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT00407186. EudraCT number: 2006-00413032.

Diagnostic variability in the histopathological assessment of advanced colorectal adenomas and early colorectal cancer in a screening population.

AIM: The aim of this study was to evaluate interobserver variability between individual pathologists and a panel of pathologists in the histopathological assessment of advanced colorectal neoplasms in the Dutch bowel cancer screening population. METHODS AND RESULTS: Histological slides of adenomas with high-grade dysplasia and early colorectal carcinomas (CRC) from 20 different laboratories were reviewed by the pathology panel of the Dutch bowel screening programme. Interobserver variability was reported by descriptive statistics. In addition, potential clinical consequences of discrepancies were evaluated. A total of 104 cases of adenomas with high-grade dysplasia and 83 early CRCs were reviewed. Discrepancies were observed in 41 of 104 (39.4%) adenoma cases, which potentially had clinical consequences in 16 (15.4%) cases. For CRC, discrepancies were shown in 44 of 83 cases (53.0%) and would have potentially led to alternative treatment strategies in 25 (30.1%) cases. Most frequently, discrepancies were observed in the assessment of lymphovascular invasion (23 of 73 cases, 31.5%). CONCLUSION: This study showed that considerable interobserver variability is present in the histopathological assessment of advanced colorectal neoplasia, which may impact upon treatment choices. Additional stains and education, as well as intercollegial consultation, might decrease this variability.

Molecular pathways in post-colonoscopy versus detected colorectal cancers: results from a nested case-control study.

BACKGROUND: Post-colonoscopy colorectal cancers (PCCRCs) pose challenges in clinical practice. PCCRCs occur due to a combination of procedural and biological causes. In a nested case-control study, we compared clinical and molecular features of PCCRCs and detected CRCs (DCRCs). METHODS: Whole-genome chromosomal copy number changes and mutation status of genes commonly affected in CRC were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status was also determined. RESULTS: In total, 122 PCCRCs and 98 DCRCs with high-quality DNA were examined. PCCRCs were more often located proximally (P < 0.001), non-polypoid appearing (P = 0.004), early stage (P = 0.009) and poorly differentiated (P = 0.006). PCCRCs showed significantly less 18q loss (FDR < 0.2), compared to DCRCs. No significant differences in mutations were observed. PCCRCs were more commonly CIMP high (P = 0.014) and MSI (P = 0.029). After correction for tumour location, only less 18q loss remained significant (P = 0.005). CONCLUSION: Molecular features associated with the sessile serrated lesions (SSLs) and non-polypoid colorectal neoplasms (CRNs) are more commonly seen in PCCRCs than in DCRCs. These together with the clinical features observed support the hypothesis that SSLs and non-polypoid CRNs are contributors to the development of PCCRCs. The future focus should be directed at improving the detection and endoscopic removal of these non-polypoid CRN and SSLs. CLINICAL TRIAL REGISTRATION: NTR3093 in the Dutch trial register ( www.trialregister.nl ).

18F-Fludeoxyglucose-Positron Emission Tomography/Computed Tomography and Laparoscopy for Staging of Locally Advanced Gastric Cancer: A Multicenter Prospective Dutch Cohort Study (PLASTIC).

Importance: The optimal staging for gastric cancer remains a matter of debate. Objective: To evaluate the value of 18F-fludeoxyglucose-positron emission tomography with computed tomography (FDG-PET/CT) and staging laparoscopy (SL) in addition to initial staging by means of gastroscopy and CT in patients with locally advanced gastric cancer. Design, Setting, and Participants: This multicenter prospective, observational cohort study included 394 patients with locally advanced, clinically curable gastric adenocarcinoma (≥cT3 and/or N+, M0 category based on CT) between August 1, 2017, and February 1, 2020. Exposures: All patients underwent an FDG-PET/CT and/or SL in addition to initial staging. Main Outcomes and Measures: The primary outcome was the number of patients in whom the intent of treatment changed based on the results of these 2 investigations. Secondary outcomes included diagnostic performance, number of incidental findings on FDG-PET/CT, morbidity and mortality after SL, and diagnostic delay. Results: Of the 394 patients included, 256 (65%) were men and mean (SD) age was 67.6 (10.7) years. A total of 382 patients underwent FDG-PET/CT and 357 underwent SL. Treatment intent changed from curative to palliative in 65 patients (16%) based on the additional FDG-PET/CT and SL findings. FDG-PET/CT detected distant metastases in 12 patients (3%), and SL detected peritoneal or locally nonresectable disease in 73 patients (19%), with an overlap of 7 patients (2%). FDG-PET/CT had a sensitivity of 33% (95% CI, 17%-53%) and specificity of 97% (95% CI, 94%-99%) in detecting distant metastases. Secondary findings on FDG/PET were found in 83 of 382 patients (22%), which led to additional examinations in 65 of 394 patients (16%). Staging laparoscopy resulted in a complication requiring reintervention in 3 patients (0.8%) without postoperative mortality. The mean (SD) diagnostic delay was 19 (14) days. Conclusions and Relevance: This study's findings suggest an apparently limited additional value of FDG-PET/CT; however, SL added considerably to the staging process of locally advanced gastric cancer by detection of peritoneal and nonresectable disease. Therefore, it may be useful to include SL in guidelines for staging advanced gastric cancer, but not FDG-PET/CT.