Prevalence and Associations of Beta2-Microglobulin Mutations in MSI-H/dMMR Cancers.

Microsatellite instability (MSI) has emerged as an important predictor of sensitivity for immunotherapy-based strategies. ß-2-Microglobulin (B2M) contains microsatellites within the coding regions and is prone to somatic changes in MSI/mismatch repair deficiency (MSI/dMMR) tumors. To delineate prevalence and associations of B2M mutations in MSI-H/dMMR cancers, we investigated the mutational profile of B2M and clinical and pathological features in gastric cancer (GC), colorectal cancer (CRC), and endometrial cancer (EC) with a high incidence of microsatellite instability-high (MSI-H)/dMMR. Formalin-fixed paraffin-embedded (FFPE) tumor tissues along with matched normal tissues were collected from 108 MSI/dMMR patients with GC, CRC, and EC. Genomic profiling of tissue and blood samples were assessed next-generation sequencing (NGS). Immunohistochemistry (IHC) was used to examine the presence or absence of B2M protein. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. NGS assay revealed that genes involved in chromatin regulation, the PI3K pathway, the WNT pathway, and mismatch repair were extensively altered in the MSI-H cohort. Signature 6 and 26, 2 of 4 mutational signatures associated with defective DNA mismatch repair, featured with high numbers of small insertion/deletions (INDEL) dominated in all 3 types of cancer. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. Tumor mutational burden (TMB) was significantly higher in the patients carrying MSI-H/dMMR tumors with B2M mutation than that in patients with wild-type B2M (P = .026).The frame shift alteration occurring at the exonic microsatellite sties caused loss of function of B2M gene. In addition, a case with CRC carrying indels in B2M gene resisted the ICI treatment was reported. In conclusion, patients carrying MSI-H/dMMR tumors with B2M mutation showed significantly higher TMB. Prescription of ICIs should be thoroughly evaluated for these patients.

Prognostic Nomograms Based on Three Lymph Node Classification Systems for Resected Gastric Adenocarcinoma: A Large Population-Based Cohort Study and External Validation.

BACKGROUNDS: The optimal lymph node classification system for prognostic assessment in gastric adenocarcinoma (GAC) patients who undergo lymph node dissection remains unclear. Therefore, this study aimed to compare prognostic nomograms based on AJCC N stage, lymph node ratio (LNR), and log odds of metastatic lymph nodes (LODDS) to evaluate the prognosis and differentiate risk subgroups of patients with resected GAC. PATIENTS AND METHODS: We collected 4633 patients with resected stage I-III GAC receiving chemotherapy from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Independent prognostic factors were selected by Cox regression analyses, based on which nomograms were constructed. External validation was performed in 228 cases from Nanjing Drum Tower Hospital. Kaplan-Meier survival analysis was used to evaluate the effect of postoperative radiotherapy (PORT) for different lymph node classifications. RESULTS: Multivariate analysis indicated that age, grade, primary site, T stage, N stage, LNR, LODDS, and radiotherapy were independent predictors. Good discrimination power and high consistency of calibration plots were obtained from the LODDS system nomogram. The LODDS classification could more precisely differentiate risk subgroups and improve the discrimination of the resected GAC prognosis. A user-friendly webserver of LODDS system was built based on the nomogram for convenient clinical application. CONCLUSIONS: The LODDS seems to be the most reliable lymph node classification in predicting the prognosis of patients with resected GAC and should be recommended in clinical prognostic assessment. Incorporating LODDS into the staging system will enable clinicians to more accurately predict prognosis and guide radiotherapy regimen decisions.

Immunotherapies targeting the oncogenic fusion gene CLDN18-ARHGAP in gastric cancer.

The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.

Macrophages reprogramming improves immunotherapy of IL-33 in peritoneal metastasis of gastric cancer.

Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33, a cytokine that is reported to potentiate antitumor immunity and inhibit metastasis. We found survival was significantly prolonged in patients with high IL-33 mRNA expression. In immunocompetent mice, intraperitoneal administration of IL-33 could induce a celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 signaling. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) had a synergistic antitumor effect. Inducing a local inflammatory milieu by IL-33 administration provided a novel approach for treating peritoneal metastasis, which, when combined with TAM reprogramming to reshape TIME, can achieve better treatment efficacy.

Effect of the age of onset on epidemiology, clinical features, and comorbidity of geriatric psoriasis.

Psoriasis is an immune-mediated chronic, relapsing, inflammatory, systemic disease induced by a combination of genetics and environment. Currently, there are limited reports on the epidemiological and clinical characteristics of geriatric psoriatic patients in mainland China. This study analyzed the epidemiological characteristics, clinical features, and comorbidity rates of geriatric patients with psoriasis and evaluated the influence of age of onset on disease characteristics. This retrospective study enrolled 1259 geriatric patients with psoriasis in hospitals affiliated with the National Standardized Psoriasis Diagnosis and Treatment Center in China from September 2011 to July 2020 to analyze the epidemiological characteristics, clinical features, and prevalence of comorbidity in geriatric psoriasis. The cases were classified according to the age of onset into two groups to compare differences: early-onset psoriasis (EOP) and late-onset psoriasis (LOP). The mean age of geriatric patients with psoriasis was 67, with a 1.8:1 male-to-female ratio and 10.7% positive family history. The clinical manifestations of plaque psoriasis accounted for a high proportion (82.0%) and 85.1% of patients had moderate to severe disease. Overweight (27.8%), hypertension (18.0%), joint involvement (15.8%), diabetes (13.7%), and coronary heart disease (4.0%) were the first five common comorbidities. The LOP group had significantly more patients (79.9%) than the EOP group (20.1%). Positive family history was significantly associated with the EOP group (21.7%) than the LOP group (7.9%). The scalp (60.2%) was the most affected area, followed by the nails (25.3%), palmoplantar region (25.0%), and genitals (12.7%). This study analyzed the epidemiological and clinical characteristics of geriatric psoriasis in China and found that age of onset had no effect on disease characteristics or other comorbidities, except for toenail involvement, diabetes, and joint damage.

Antigen-Specific T Cell Immunotherapy Targeting Claudin18.2 in Gastric Cancer.

T cell-based immunotherapy has led to many breakthroughs in the treatment of solid tumors. In this study, we found that membrane protein Claudin18.2 was a promising antigen in T cell-based immunotherapy for gastric cancer (GC). Firstly, we identified five HLA-A*0201- and seven HLA-A*1101-restricted T cell epitopes of Claudin18.2. Peripheral blood mononuclear cells (PBMCs) stimulated by Claudin18.2 peptides showed progressive anti-tumor ability and higher effective cytokine secretion than unstimulated PBMCs in vitro. In total, 81.8% of GC patients were Claudin18.2-positive by immunohistochemical (IHC) detection, and a positive correlation between Claudin18.2 expression and peptide reactivity (p = 0.002) was found. Clinicopathological features analyses demonstrated that Claudin18.2 expression did not correlate with gender, age, stage or Lauren classification. Survival analysis showed that a longer median progression-free survival (mPFS) was not related to peptide reactivity (p = 0.997), but related to a lower Claudin18.2 expression level (p = 0.047). These findings establish a foundation for the clinical application of Claudin18.2 targeted T cell-based immunotherapy in GC.

Loss of ARID1A expression is associated with systemic inflammation markers and has important prognostic significance in gastric cancer.

BACKGROUND: The tumor suppressor gene AT-rich interactive domain 1A (ARID1A) and systemic inflammatory response (SIR) have been reported to be related to the sensitivity to immunotherapy. This study intended to explore the relationship between ARID1A expression and SIR, and to further elucidate the prognostic value of ARID1A expression in gastric cancer (GC). METHODS: The mRNA and protein expression of ARID1A were detected in 272 formalin-fixed paraffin-embedded (FFPE) tumor tissues. The data of nine systemic inflammation markers were collected 1 week before gastrectomy. Univariate and multivariate COX analysis were used to screen out independent predictors of GC. RESULTS: Negative expression of ARID1A protein was related to GC with deficient mismatch repair (dMMR) (p = 0.033), positive programmed cell death-ligand 1 (PD-L1) (p = 0.005) and lower albumin level (p = 0.0064). Low expression of ARID1A mRNA was common in GC with abnormal E-cadherin (p = 0.020) and a higher platelet/lymphocyte ratio (PLR) (p = 0.0391). Multivariate COX analysis showed that the expression of ARID1A protein (p = 0.023), age (p = 0.004), T stage (p = 0.009) and N stage (p = 0.009) were independent predictors of GC. The nomogram established by independent predictors can accurately evaluate the survival risk of patients with GC. CONCLUSIONS: The loss of ARID1A protein expression was associated with the dMMR subtype and high expression of PD-L1 in GC. Negative ARID1A protein and low expression of mRNA were associated with aberrant systemic inflammatory markers. The expression of ARID1A protein had important prognostic significance in GC.

DKK1 Promotes Tumor Immune Evasion and Impedes Anti-PD-1 Treatment by Inducing Immunosuppressive Macrophages in Gastric Cancer.

Tumor-associated macrophages (TAM) have key functions in promoting a suppressive tumor immune microenvironment (TIME) and immune evasion, which largely limit treatment effects of immune-checkpoint inhibitors (ICI) in different cancers, including gastric cancer. Dickkopf-1 (DKK1) is associated with tumor progression and has been shown to negatively regulate antitumor immunity, but the impact of DKK1 on the TIME remains incompletely understood. Here, we found that tumoral DKK1 expression is closely associated with worse survival and a suppressive TIME in gastric cancer patients. Results from in vitro coculture assays suggested that DKK1 induces macrophages to become immunosuppressive, thereby inhibiting antitumor responses of CD8+ T cells and natural killer (NK) cells. In vivo DKK1 blockade in syngeneic gastric cancer mouse models reprogramed TAMs to restore the immune activity in the TIME and triggered significant tumor regression. DKK1 blockade also directly reduced the growth of human gastric cancer tumors with high DKK1 expression in a xenograft model. Mechanistically, DKK1 interacted with cytoskeleton-associated protein 4 (CKAP4) on the macrophage surface and activated downstream PI3K-AKT signaling, which contributed to immune suppression. TAM reprogramming by DKK1 blockade also augmented the efficacy of programmed cell death protein-1 (PD-1) blockade in gastric cancer models. Therefore, our study provides novel insights into the role of DKK1 on tumor-intrinsic, innate, and adaptive antitumor immunity modulation and suggests that DKK1 is a promising immunotherapeutic target for enhanced PD-1 blockade therapy in gastric cancer.

Individualized prediction of survival benefits from perioperative chemoradiotherapy for patients with resectable gastric cancer.

BACKGROUND: The survival benefits of perioperative chemoradiotherapy (PCRT) and perioperative chemotherapy (PCT) for resectable gastric cancer (GC) patients remain unclear. This study aimed to compare the effects of PCRT and PCT in patients with resectable GC and develop a nomogram to evaluate the prognosis and disease risk of patients. METHODS: A total of 6890 patients with stage IB-IIIC GC from 2010 to 2015 were retrieved from the Surveillance, Epidemiology and End Results (SEER) database. Univariate Cox proportional hazards regression analyses were performed to evaluate the prognostic value of involved variables. A new nomogram was constructed based on development cohort and validated by an external validation cohort. The clinical practicability and accuracy were assessed by concordance index (C-index), calibration plot, and receiver operating characteristic (ROC) curve. RESULTS: A better prognosis was obtained for patients with stage III GC treated with PCRT compared with those treated with PCT. Additionally, patients with grade III/IV, diffuse type GC, distal gastric cancer (DGC), tumor size >34 millimeters, or positive lymph nodes were more likely to benefit from PCRT. Multivariate analyses indicated that age, grade, tumor size, T stage, N stage, and comprehensive treatment were independent covariates. Excellent agreement of calibration plots and good discrimination power were obtained using the nomogram. The nomogram achieved a better net benefit than the 8th edition AJCC TNM staging. An online version was built based on the nomogram for convenient clinical use. CONCLUSION: The application of perioperative chemoradiotherapy should be determined according to the clinicopathological features of patients. Our nomogram provided a reliable tool for screening patients who were right for PCRT and evaluating individual survival benefits.

Double-edged role of radiotherapy in patients with pulmonary large-cell neuroendocrine carcinoma.

Purpose: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is classified as non-small-cell lung cancer, but has characteristics similar to small-cell lung cancer. This study was performed to evaluate the effect of surgery and radiotherapy on patients with LCNEC. Materials and Methods: We analyzed 1,619 patients with stage I-III LCNEC, identified from the Surveillance, Epidemiology, and End Results database, diagnosed from 2000 to 2013. The Kaplan-Meier analysis and the Cox proportional hazard model were used to study patient prognosis. Results: Overall, 869 (53.7%) stage I LCNEC patients, 203 (12.5%) stage II patients, and 547 (33.8%) stage III patients were included in the analysis. Various surgery types were all associated with higher overall survival (OS) and lung cancer-specific survival (LCSS) than no surgery, with the following HRs: 0.334 (OS) and 0.279 (LCSS) for lobectomy, 0.468 (OS) and 0.416 (LCSS) for partial/wedge/segmental resection, and 0.593 (OS) and 0.522 (LCSS) for pneumonectomy (all p < 0.05). OS and LCSS of stage I and II LCNEC patients were not improved by radiotherapy (stage I: OS p = 0.719, LCSS p = 0.557; stage II: OS p = 0.136, LCSS p = 0.697). However, in stage III patients, radiotherapy significantly improved both OS and LCSS (p < 0.001). Following multivariate analysis, increased age, male patients, radiotherapy and diagnosed at stage II or III were all independent risk factors for LCNEC (all p < 0.05). Conclusion: Lobectomy had the best outcome for OS and LCSS in stage I-II LCNEC. For stage III LCNEC patients, radiotherapy can significantly improve survival time. However, in LCNEC patients undergoing surgery, radiotherapy may reduce survival time.

Survival Outcomes for Patients with Surgical and Non-Surgical Treatments in Stages I-III Small-Cell Lung Cancer.

Objectives: Chemotherapy and radiation therapy are the standard treatments for patients with small-cell lung cancer (SCLC). However, recent studies suggest that patients with limited stage (I-III) SCLC may benefit from surgical treatment. This study was performed to evaluate the survival outcomes of surgery for stage I-III SCLC. Methods: This analysis used data from the Surveillance, Epidemiology, and End Results (SEER) database. All stage I-III (excluding N3 and Nx) SCLC patients received a diagnosis between 2004 and 2014. Overall survival (OS) and lung cancer-specific survival (LCSS) were determined by Kaplan-Meier analysis and compared using the log-rank test. A Cox proportional hazard model identified relevant survival variables. Results: A total of 4,780 histologically confirmed patients were identified from the SEER database, comprising 1,018 patients (21.3%) with stage I disease; 295 (6.2%) with stage II; and 3,467 (72.5%) with stage III disease. Among all of the patients, 520 had been treated with surgery, the majority (n = 344; 66.2%) of whom had stage I disease. The hazard ratio (HR) for OS and LCSS, in patients who underwent surgery, according to stage were as follows: OS, 0.369 and LCSS, 0.335 in stage I; OS, 0.549 and LCSS, 0.506 in stage II; and OS, 0.477 and LCSS, 0.456 in stage III (all p < 0.001). Patients who underwent surgery had significantly better OS, and lobectomy was associated with the best outcome. Conclusions: Surgical resection was associated with significantly improved OS outcomes and should be considered in the management of stage I-III SCLC.

Diagnostic and prognostic value of blood samples for KRAS mutation identification in lung cancer: a meta-analysis.

Circulating tumor DNA (ctDNA) and tumor cells (CTC) are novel approaches for identifying genomic alterations. Thus, we designed a meta-analysis to evaluate the diagnostic value and prognostic significance of a KRAS proto-oncogene, GTPase (KRAS) mutation for lung cancer patients. All included articles were from PubMed, EMBASE, Web of Science and Cochrane Library. Twelve articles that described 1,131 patients were reviewed. True positives (TP), false positives (FP), true negatives (TN), and false negatives (FN) were used to calculate pooled sensitivity, specificity, the positive likelihood ratio (PLR), the negative likelihood ratio (NLR), a diagnostic odds ratio (DOR), the area under the curve (AUC) and corresponding 95% confidence intervals (95% CI). PLR is calculated as sensitivity/(1-specificity) and NLR is (1- sensitivity)/specificity. DOR is a measured of diagnostic effectiveness (PLR/NLR). A survival analysis subgroup was also designed to evaluate prognostic significance. Pooled sensitivity, specificity, PLR, NLR, DOR and AUC were 0.79 (95% CI, 0.63-0.89), 0.93 (95% CI, 0.89-0.96), 12.13 (92% CI, 7.11-20.67), 0.22 (95% CI, 0.12-0.41), 54.82 (95% CI, 23.11-130.09), and 0.95 (95% CI, 0.93-0.96), respectively. KRAS mutation and wild-type hazard ratios for overall survival and progression-free survival were 1.37 (95% CI, 1.08-1.66), 1.46 (95% CI, 1.15-1.77) in blood samples, and 1.16 (95% CI, 1.03-1.28), 1.28 (95% CI, 1.09-1.46) in tumor tissue.

Prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma.

PURPOSE: Gastric carcinoma (GC) is a highly aggressive cancer and one of the leading causes of cancer-related deaths worldwide. Histopathological evaluation pertaining to invasiveness is likely to provide additional information in relation to patient outcome. In this study, we aimed to evaluate the prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma. MATERIALS AND METHODS: Hematoxylin and eosin-stained slides generated from 296 gastric adenocarcinoma patients with full clinical and pathological and follow-up information were systematically reviewed. The patients were grouped on the basis of tumor budding, single cell invasion, large cell invasion, mitotic count, and fibrosis. The association between histopathological parameters, different classification systems, and overall survival (OS) was statistically analyzed. RESULTS: Among the 296 cases that were analyzed, high-grade tumor budding was observed in 49.0% (145) of them. Single cell invasion and large cell invasion were observed in 62.8% (186) and 16.9% (50) of the cases, respectively. Following univariate analysis, patients with high-grade tumor budding had shorter OS than those with low-grade tumor budding (hazard ratio [HR]: 2.260, P<0.001). Similarly, the OS of patients with single cell invasion and large cell invasion was reduced (single cell invasion, HR: 3.553, P<0.001; large cell invasion, HR: 2.466, P<0.001). Following multivariate analysis, tumor budding and single cell invasion were observed to be independent risk factors for gastric adenocarcinoma (P<0.05). According to the Lauren classification, patients with intestinal-type adenocarcinoma had better outcomes than those with diffuse-type adenocarcinoma (HR: 2.563, P<0.001). CONCLUSION: Tumor budding and single cell invasion in gastric adenocarcinoma are associated with an unfavorable prognosis.

Subcellular localization of ß-arrestin1 and its prognostic value in lung adenocarcinoma.

ß-Arrestins play important roles in cancer progression, and the subcellular localization of ß-arrestin1 has been receiving increasingly more attention. Intriguingly, several studies, including some of our previous work, showed that the effects of ß-arrestin1 on outcomes of cancer patients were controversial.Specimens were obtained from 133 patients with lung adenocarcinoma. Immunohistochemistry was used to detect the expression of ß-arrestin1 and p300 in the collected tissues. The Kaplan-Meier analysis and Cox proportional hazards regression were used to examine the relationship between ß-arrestin1 and patient survival.We found no significant association between ß-arrestin1 and clinicopathological variables. The Kaplan-Meier plot showed that patients with high expression of ß-arrestin1 (especially in the nucleus) had a poorer overall survival (OS) and shorter disease-free survival (DFS) (P = .026, P = .015). Additionally, high p300 expression also resulted in worse OS (P = .039). Following the univariate analysis, high expressions of nuclear ß-arrestin1 and p300 were classed as poor prognostic factors for both OS (P = .016) and DFS (P = .025).The expression of ß-arrestin1 in the nucleus is associated with increased malignant tendency of lung adenocarcinoma, and the predictive value of ß-arrestin1 may be optimized by combining information about the expression of p300 acetyltransferase.