Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
1.
Breast Cancer ; 2024 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-38643429

RESUMEN

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low status has recently gained attention because of the potential therapeutic benefits of antibody-drug conjugates (ADCs) in breast cancer patients. We aimed to investigate the concordance of HER2 status between core needle biopsy (CNB) and subsequent surgical resection specimens focusing on the HER2-low status. METHODS: This retrospective study was conducted in 1,387 patients with invasive breast cancer whose HER2 status was evaluated in both CNB and surgical resection specimens. The discordance rates between CNB and surgical resection specimens and the clinicopathological features associated with HER2 status discordance were analyzed. RESULTS: The overall concordance rates of HER2 status between CNB and surgical resection specimens were 99.0% (κ = 0.925) for two-group classification (negative vs. positive) and 78.5% (κ = 0.587) for three-group classification (zero vs. low vs. positive). The largest discordance occurred in CNB-HER2-zero cases with 42.8% of them reclassified as HER2-low in surgical resection. HER2 discordance was associated with lower histologic grade, tumor multiplicity, and luminal A subtype. In multivariate analysis, tumor multiplicity and estrogen receptor (ER) positivity were independent predictive factors for HER2-zero to low conversion. CONCLUSIONS: Incorporation of HER2-low category in HER2 status interpretation reduces the concordance rate between CNB and surgical resection specimens. Tumor multiplicity and ER positivity are predictive factors for conversion from HER2-zero to HER2-low status. Therefore, HER2 status should be re-evaluated in resection specimens when considering ADCs in tumors exhibiting multiplicity and ER positivity.

2.
Cancer Res Treat ; 56(1): 219-237, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37591783

RESUMEN

PURPOSE: Bone metastasis (BM) adversely affects the prognosis of gastric cancer (GC). We investigated molecular features and immune microenvironment that characterize GC with BM compared to GC without BM. MATERIALS AND METHODS: Targeted DNA and whole transcriptome sequencing were performed using formalin-fixed paraffin-embedded primary tumor tissues (gastrectomy specimens) of 50 GC cases with distant metastases (14 with BM and 36 without BM). In addition, immunohistochemistry (IHC) for mucin-12 and multiplex IHC for immune cell markers were performed. RESULTS: Most GC cases with BM had a histologic type of poorly cohesive carcinoma and showed worse overall survival (OS) than GC without BM (p < 0.05). GC with BM tended to have higher mutation rates in TP53, KDR, APC, KDM5A, and RHOA than GC without BM. Chief cell-enriched genes (PGA3, PGC, and LIPF), MUC12, MFSD4A, TSPAN7, and TRIM50 were upregulated in GC with BM compared to GC without BM, which was correlated with poor OS (p < 0.05). However, the expression of SERPINA6, SLC30A2, PMAIP1, and ITIH2 were downregulated in GC with BM. GC with BM was associated with PIK3/AKT/mTOR pathway activation, whereas GC without BM showed the opposite effect. The densities of helper, cytotoxic, and regulatory T cells did not differ between the two groups, whereas the densities of macrophages were lower in GC with BM (p < 0.05). CONCLUSION: GC with BM had different gene mutation and expression profiles than GC without BM, and had more genetic alterations associated with a poor prognosis.


Asunto(s)
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Perfilación de la Expresión Génica , Pronóstico , Transcriptoma , Genómica , Microambiente Tumoral , Proteína 2 de Unión a Retinoblastoma/genética
3.
Genomics Inform ; 21(2): e24, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37704210

RESUMEN

Assays of clinical diagnosis and species identification using molecular markers are performed according to a quantitative method in consideration of sensitivity, cost, speed, convenience, and specificity. However, typical polymerase chain reaction (PCR) assay is difficult to quantify and have various limitations. In addition, to perform quantitative analysis with the quantitative real-time PCR (qRT-PCR) equipment, a standard curve or normalization using reference genes is essential. Within the last a decade, previous studies have reported that the digital PCR (dPCR) assay, a third-generation PCR, can be applied in various fields by overcoming the shortcomings of typical PCR and qRT-PCR assays. We selected Stilla Naica System (Stilla Technologies), Droplet Digital PCR Technology (Bio-Rad), and Lab on an Array Digital Real-Time PCR analyzer system (OPTOLANE) for comparative analysis among the various droplet digital PCR platforms currently in use commercially. Our previous study discovered a molecular marker that can distinguish Hanwoo species (Korean native cattle) using Hanwoo-specific genomic structural variation. Here, we report the pros and cons of the operation of each dPCR platform from various perspectives using this species identification marker. In conclusion, we hope that this study will help researchers to select suitable dPCR platforms according to their purpose and resources.

4.
J Gastric Cancer ; 23(2): 264-274, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37129151

RESUMEN

PURPOSE: In this study, polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing was comprehensively analyzed and compared with immunohistochemistry (IHC) for mismatch repair (MMR) protein expression in patients with gastric cancer (GC). MATERIALS AND METHODS: In 5,676 GC cases, PCR-based MSI testing using five microsatellites (BAT-26, BAT-25, D5S346, D2S123, and D17S250) and IHC for MLH1 were performed. Re-evaluation of MSI testing/MLH1 IHC and additional IHC for MSH2, MSH6, and PMS2 were performed in discordant/indeterminate cases. RESULTS: Of the 5,676 cases, microsatellite stable (MSS)/MSI-low and intact MLH1 were observed in 5,082 cases (89.5%), whereas MSI-high (MSI-H) and loss of MLH1 expression were observed in 502 cases (8.8%). We re-evaluated the remaining 92 cases (1.6%) with a discordant/indeterminate status. Re-evaluation showed 1) 37 concordant cases (0.7%) (18 and 19 cases of MSI-H/MMR-deficient (dMMR) and MSS/MMR-proficient (pMMR), respectively), 2) 6 discordant cases (0.1%) (3 cases each of MSI-H/pMMR and MSS/dMMR), 3) 14 MSI indeterminate cases (0.2%) (1 case of dMMR and 13 cases of pMMR), and 4) 35 IHC indeterminate cases (0.6%) (22 and 13 cases of MSI-H and MSS, respectively). Finally, MSI-H or dMMR was observed in 549 cases (9.7%), of which 47 (0.8%) were additionally confirmed as MSI-H or dMMR by re-evaluation. Sensitivity was 99.3% for MSI testing and 95.4% for MMR IHC. CONCLUSIONS: Considering the low incidence of MSI-H or dMMR, discordant/indeterminate results were occasionally identified in GCs, in which case complementary testing is required. These findings could help improve the accuracy of MSI/MMR testing in daily practice.

5.
Cancer Med ; 12(9): 10371-10384, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36916290

RESUMEN

BACKGROUND: We aimed to determine the molecular and immune microenvironment characteristics of HER2-positive gastric cancer (GC) related to the patient's response to first-line trastuzumab-based treatment. METHODS: Eighty-three cases of HER2-positive advanced gastric adenocarcinoma patients treated with trastuzumab were enrolled. Targeted deep sequencing and transcriptome analysis were performed on selected 21 cases (exploration cohort) along with two post-treatment samples. The results were compared between patients progressed before 6 months (Group 2) and others (Group 1), and were validated by FISH and immunohistochemistry in total cohort. Tumor-infiltrating immune cells were evaluated using RNA sequencing data and multiplex immunohistochemistry. Progression-free survival (PFS) analysis was performed. RESULTS: Group 1 showed frequent amplification of G1/S cell cycle checkpoint-related genes and upregulated KEGG pathways related to cell proliferation. In contrast, Group 2 had more frequent EGFR, HER3, and MET amplification and higher RNA expression in immune-related KEGG pathways than Group 1. In total cohort, significant predictors of better PFS were cell cycle-related including CCNE1 amplification, Cyclin A and PLK1 overexpression, and decreased Cyclin D3 and HER3 expression (p < 0.05), or immune-related including high density of CD3- CD57+ NK cells and PD-L1 combined positive score ≥5 (p < 0.05). The best prognostic predictors were a combination of Cyclin A, Cyclin E, p21, and HER3 (p < 0.001). CONCLUSION: HER2-positive GC with favorable response to trastuzumab were characterized by cell cycle-related gene alterations and increased CD3- CD57+ NK cell infiltration. These findings would be helpful to the fine modulation of therapeutic strategies for patients with HER2-positive GC.


Asunto(s)
Neoplasias Gástricas , Humanos , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Receptor ErbB-2/metabolismo , Pronóstico , Proliferación Celular , Microambiente Tumoral
6.
Int J Med Sci ; 20(2): 232-237, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36794156

RESUMEN

Chewing is beneficial not only for digestion and absorption of food, but also for various physiological functions, such as cognition and immunity. In this study, the effect of chewing on hormonal changes and the immune response was investigated under fasting conditions in mice. We investigated leptin and corticosterone levels, which are hormones with well-known associations with immune response and large changes during fasting. To study of effects of chewing under fasting conditions, one group of mice was provided with wooden sticks to stimulate chewing, one group was supplemented with 30% glucose solution, and one group received both treatments. We examined changes in serum leptin and corticosterone levels after 1 and 2 d of fasting. Antibody production was measured 2 weeks after subcutaneous immunization with bovine serum albumin on the last day of fasting. Under fasting conditions, serum leptin levels decreased and serum corticosterone levels increased. Supplementation with 30% glucose solution during fasting increased leptin levels above normal, but had little effect on corticosterone levels. In contrast, chewing stimulation inhibited the increase in corticosterone production, but did not affect the decrease in leptin levels. Antibody production significantly increased under separate and combined treatments. Taken together, our results showed that chewing stimulation during fasting inhibited the increase in corticosterone production and improved antibody production after immunization.


Asunto(s)
Leptina , Masticación , Ratones , Animales , Corticosterona , Formación de Anticuerpos , Ayuno , Glucosa
7.
Sci Rep ; 12(1): 2295, 2022 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-35145164

RESUMEN

Epithelial-mesenchymal transition (EMT)-related cancers generally elicit low immune responses. EMT is regulated by several microRNAs (miRNAs) in cancers. Thus, this study aimed to evaluate the prognostic potential of EMT-related miRNAs as biomarkers in colorectal cancer (CRC). Formalin-fixed paraffin-embedded tumor and normal tissue and plasma samples were obtained from 65 patients with pathologically confirmed CRC. In addition, plasma samples were obtained from 30 healthy volunteers. Immunohistochemical staining for E-cadherin, ZEB1, PD-1, PD-L1, CD3, CD4, CD8, Foxp3, and CD68 was conducted on tissue samples. Droplet digital polymerase chain reaction (ddPCR) analysis was performed to evaluate miR-21-5p, 34a-5p, 138-5p, 200a-3p, 200b-5p, 200c-3p, 630, 1246, and 1290 expression in tissue samples and miR-630, 1246, and 1290 expression in plasma samples. miR-21-5p, 34a-5p, 630, 1246, and 1290 expression was higher in tumor tissues than in normal tissues (P < 0.05). EMT was significantly associated with reduced tumor-infiltrating T cells. Moreover, miR-21-5p, miR-34a-5p, miR-200a-3p, and miR-200c-3p expression was negatively correlated with T cell density (P < 0.05). High tissue levels of miR-200c-3p were associated with poor overall survival (OS) (P < 0.001). CRC patients with the EMT phenotype had poor OS; however, PD-L1 positivity and abundant PD-1 positive immune cells were correlated with better OS (P < 0.05). miR-1246 and miR-1290 levels were significantly higher in the plasma of patients with CRC than in the plasma of healthy controls (P < 0.05). High plasma levels of miR-1290 were correlated with advanced stage and poor OS (P < 0.05). The tissue expression of miR-200c-3p and plasma levels of miR-1290 measured by ddPCR indicate their potential as prognostic biomarkers for CRC.


Asunto(s)
Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/diagnóstico , MicroARNs/sangre , MicroARNs/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/fisiopatología , Transición Epitelial-Mesenquimal/genética , Femenino , Expresión Génica/genética , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Pronóstico
8.
J Transl Med ; 19(1): 529, 2021 12 24.
Artículo en Inglés | MEDLINE | ID: mdl-34952595

RESUMEN

BACKGROUND: Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). METHODS: We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. RESULTS: Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. CONCLUSIONS: Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.


Asunto(s)
Neoplasias Gástricas , Humanos , Inmunohistoquímica , Células Asesinas Naturales , Pronóstico , Neoplasias Gástricas/patología
9.
Oncoimmunology ; 10(1): 1954761, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34367732

RESUMEN

We sought to determine the clinicopathological significance of PD-1, LAG3, and TIM3 in gastric cancer (GC) by examining their expression and immune context. Immunohistochemistry (IHC) for PD-1, TIM3, LAG3, and tumor-infiltrating immune cell (TIIC) markers was performed in 385 stage II/III GCs. Epstein-Barr virus (EBV) and microsatellite stability (MSI) testing were performed for molecular classification. Chromogenic multiplex IHC (mIHC) for PD1, TIM3, LAG3, CD3, CD8, FOXP3, CD68, and cytokeratin was performed in 58 of the total samples. PD-1, LAG3, and TIM3 expression in TIICs was observed in 91 (23.6%), 193 (50.1%), and 257 (66.8%) GCs by single IHC, respectively. The expression was associated with EBV+ and MSI-H molecular subtypes (p ≤ 0.001). A positive expression of LAG3 in the invasive margin of the tumor was associated with better prognosis in univariate (p = .020) and multivariate (p = .026) survival analyses. The expression of different immune checkpoint receptors (ICRs) was significantly positively correlated. Dual or triple ICR expression was more frequent in high PD-1 and TIM3 density groups than in low-density groups by mIHC (all p ≤ 0.05). ICRs were mainly expressed in CD3+CD8+ and CD3+CD8- T cells. Fifty-eight GCs were classified into three groups by clustering analysis based on mIHC, and the group with the highest ICR expression in TIICs showed significantly better outcomes in progression-free survival (p = .020). In GC, PD-1, LAG3, and TIM3 expression is positively correlated and associated with better prognosis. Our study provides information for the application of effective immune checkpoint inhibitors against GC.


Asunto(s)
Antígenos CD/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias Gástricas , Infecciones por Virus de Epstein-Barr , Receptor 2 Celular del Virus de la Hepatitis A/genética , Herpesvirus Humano 4 , Humanos , Inmunohistoquímica , Linfocitos Infiltrantes de Tumor , Receptor de Muerte Celular Programada 1/genética , Neoplasias Gástricas/diagnóstico , Proteína del Gen 3 de Activación de Linfocitos
10.
Cancer Sci ; 112(1): 91-100, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33159376

RESUMEN

Downregulation of human leukocyte antigen (HLA) class I has been postulated to be a mechanism of adaptive immune escape in various tumors, especially microsatellite instability-high (MSI-H) colorectal cancer (CRC). In this study, we aimed to investigate HLA class I and ß2-microglobulin (ß2M) expression in MSI-H and microsatellite-stable (MSS) CRCs and determine its prognostic impact. The representative areas from the tumor center (TC) and tumor periphery (TP) from 300 CRCs, including 161 MSI-H and 139 MSS cases, were selected to construct a tissue microarray. Immunohistochemistry (IHC) for HLA A/B/C, ß2M, CD3, and CD8 was performed. Reduced HLA A/B/C expression was detected in 113 (70.2%) MSI-H and 54 (38.8%) MSS cases, while reduced ß2M expression was observed in 69 (42.9%) MSI-H and 17 (12.2%) MSS cases. Although reduced ß2M expression was associated with higher pathological tumor (pT) stage in MSI-H CRC with borderline significance, no association was found between HLA A/B/C and ß2M expression and survival. Interestingly, reduced HLA A/B/C expression in MSS was associated with higher stage, and reduced HLA A/B/C and ß2M expression was an independent prognostic factor in multivariate analysis. In conclusion, reduced HLA A/B/C and ß2M expression was frequently observed in immunotherapy-naive MSI-H CRC, suggesting the possibility of primary resistance to immune checkpoint inhibitor. Interestingly, downregulation of HLA A/B/C and ß2M was associated with poor prognosis in MSS cancers. Overall, IHC for HLA A/B/C and ß2M might be a feasible predictive or prognostic tool in CRC.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Antígenos de Histocompatibilidad Clase I/genética , Microglobulina beta-2/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Regulación hacia Abajo/genética , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Inestabilidad de Microsatélites , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Pronóstico , Adulto Joven
11.
J Pathol Transl Med ; 54(5): 378-386, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32601264

RESUMEN

BACKGROUND: Recently, molecular classifications of gastric cancer (GC) have been proposed that include TP53 mutations and their functional activity. We aimed to demonstrate the correlation between p53 immunohistochemistry (IHC) and TP53 mutations as well as their clinicopathological significance in GC. METHODS: Deep targeted sequencing was performed using surgical or biopsy specimens from 120 patients with GC. IHC for p53 was performed and interpreted as strong, weak, or negative expression. In 18 cases (15.0%) with discrepant TP53 mutation and p53 IHC results, p53 IHC was repeated. RESULTS: Strong expression of p53 was associated with TP53 missense mutations, negative expression with other types of mutations, and weak expression with wild-type TP53 (p<.001). The sensitivity for each category was 90.9%, 79.0%, and 80.9%, and the specificity was 95.4%, 88.1%, and 92.3%, respectively. The TNM stage at initial diagnosis exhibited a significant correlation with both TP53 mutation type (p=.004) and p53 expression status (p=.029). The Kaplan-Meier survival analysis for 109 stage II and III GC cases showed that patients with TP53 missense mutations had worse overall survival than those in the wild-type and other mutation groups (p=.028). Strong expression of p53 was also associated with worse overall survival in comparison to negative and weak expression (p=.035). CONCLUSIONS: Results of IHC of the p53 protein may be used as a simple surrogate marker of TP53 mutations. However, negative expression of p53 and other types of mutations of TP53 should be carefully interpreted because of its lower sensitivity and different prognostic implications.

12.
Br J Cancer ; 122(9): 1399-1408, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32203213

RESUMEN

BACKGROUND: The aim of the study was to determine the human leucocyte antigen class-I (HLA-I), programmed death-ligand 1 (PD-L1) expression and tumour-infiltrating lymphocytes (TILs) of microsatellite instability-high gastric cancer. METHODS: The HLA-I expression type was determined by immunohistochemistry of HLA-A, HLA-B, HLA-C and ß2-microglobulin in the centre of the tumour (CT) and in the invasive margin (IM) of samples from 293 patients (total loss vs. preserved type). PD-L1 expression and TIL density was examined immunohistochemically. HLA-I genotyping was also performed. RESULTS: The expression loss of the HLA-I molecules was significantly associated with low TIL density. According to survival analyses, the HLA-I expression type and PD-L1 positivity were not independent prognostic factors. The TIL density had no prognostic implication when survival analysis was performed for the whole patient group; however, high CD8+ TIL infiltration was significantly associated with good prognosis in only HLA-I-preserved-type/PD-L1-positive group (p = 0.034). The homozygosity of the HLA-I allele was more frequently observed in the total loss type group. CONCLUSIONS: We confirmed differential prognostic implication of CD8+ TILs according to the HLA-I and PD-L1 expression. Determination of the HLA-I expression could be helpful to select patients who would benefit from anti-PD-1/PD-L1 therapy.


Asunto(s)
Antígeno B7-H1/genética , Inestabilidad de Microsatélites , Receptor de Muerte Celular Programada 1/genética , Neoplasias Gástricas/genética , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Supervivencia sin Enfermedad , Femenino , Genotipo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología
13.
Cancer Res Treat ; 52(3): 661-670, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32019283

RESUMEN

PURPOSE: We provide a comparison between 22C3 pharmDx and SP263 assay, for evaluating programmed death ligand 1 (PD-L1) expression in advanced gastric cancer (GC) patients. MATERIALS AND METHODS: The PD-L1 immunohistochemistry by 22C3 pharmDx and SP263 assays was performed in the center of the tumor (CT) and invasive margin (IM) in 379 GC tissues using tissue microarrays and interpreted as combined positive score (CPS) and tumor proportion score (TPS). Of the total samples, 55 samples were independently reviewed by five pathologists. RESULTS: The two assays showed a high correlation in both the CPS and TPS. At a CPS ≥ 1 cut-off, 219 (57.8%) and 231 (60.9%) GCs were positive for PD-L1 with the 22C3 and SP263 assays, and at ≥ 10 cut-off, 37 (9.8%) and 36 (9.5%) GCs were positive, respectively. The overall percent agreement (OPA) was greater than 90% with CPS ≥ 1 and ≥ 10 cut-offs, and TPS ≥ 1% and ≥ 10% cut-offs. There was higher OPA between the two assays with a CPS cut-off ≥ 10 (99.2%) than ≥ 1 (94.7%). The percent agreement between the CT and IM was higher with a CPS cut-off ≥ 10 (92.9%) than ≥ 1 (77.6%). Patient with positive expression at CPS ≥ 5 cut-off had a significantly better outcomes in both assays. Interobserver variability among five pathologists was higher than the assay variability. CONCLUSION: Two assays for PD-L1 expression in GC showed high agreement. These results provide guidance for selecting eligible patients with GC for pembrolizumab treatment.


Asunto(s)
Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Inmunohistoquímica/métodos , Selección de Paciente , Juego de Reactivos para Diagnóstico/estadística & datos numéricos , Neoplasias Gástricas/diagnóstico , Toma de Decisiones Clínicas , Humanos , Valor Predictivo de las Pruebas , Juego de Reactivos para Diagnóstico/clasificación , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/metabolismo
14.
Cancer Immunol Immunother ; 68(11): 1779-1790, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31620857

RESUMEN

Human leukocyte antigen class I (HLA I) molecules composed of alpha (heavy) chain, including HLA-A, -B, or -C encoded by HLA genes, and beta-2-microglobulin (ß2M) are membrane proteins on all nucleated cells that display peptide antigens for recognition by CD8-positive cytotoxic T cells. Here, we examined the clinicopathologic signification of HLA I expression in patients with gastric cancer (GC). Immunohistochemistry was performed to detect HLA A/B/C, ß2M, CD8, p53, and programmed death-ligand 1 (PD-L1) in the center and invasive margin of the tumor in 395 stage II and III GCs using tissue array method. Additionally, Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status were investigated. Negative expression of HLA A/B/C and ß2M was observed in 258 (65.3%) and 235 (59.5%) of 395 stage II and III GCs, respectively. Negative HLA I expression was significantly associated with aggressive clinicopathologic features. Furthermore, negative expression of HLA A/B/C and ß2M was inversely correlated with CD8-positive cytotoxic T cell infiltration, EBV-positivity, and PD-L1 expression (all p < 0.001). Patients with HLA A/B/C-negative GC had worse overall survival (OS) (p = 0.019) and combined analysis with both HLA A/B/C and ß2M expression status significantly predicted OS in univariate (p = 0.004) and multivariate survival analysis (p = 0.016). Negative expression of HLA A/B/C and ß2M was frequently observed in stage II and III GCs, particularly with the aggressive clinicopathologic features, and correlated with an unfavorable prognosis and host immune response status. These findings contribute to further development of immunotherapy.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Antígenos HLA/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Gástricas/patología , Microambiente Tumoral/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/inmunología , Femenino , Estudios de Seguimiento , Antígenos HLA/inmunología , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/cirugía , Adulto Joven , Microglobulina beta-2/inmunología , Microglobulina beta-2/metabolismo
15.
J Cancer ; 10(13): 3070-3078, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31281485

RESUMEN

Programmed death ligand 1 (PD-L1) expression provides significant value to predict prognosis and response following immunotherapy in several types of cancers. However, its clinicopathological and prognostic significance in melanoma remains unclear. PD-L1 and the number of tumor infiltrating lymphocytes (TILs) were investigated in 63 Korean patients with melanoma based on the melanoma scoring system. We also compared the results using the PD-L1 antibodies-22C3 and E1L3N clones. In addition, BRAF gene mutation was detected using anti-BRAF antibody and real-time polymerase chain reaction. Overall, 29 (46.0%), 16 (25.4%), and 18 (28.6%) patients exhibited the acral lentiginous type, nodular type, and other histological subtypes of melanoma, respectively. PD-L1 expression was detected in 37 (58.7%) cases and was closely associated with a CD8+TILhigh phenotype (P < 0.001). Combined survival analysis depending on PD-L1 and CD8+TILs status showed that the PD-L1-/CD8+TILhigh group demonstrated the best survival outcome, whereas patients with PD-L1+/CD8+ TILlow showed the worst prognosis (P = 0.039). However, PD-L1+/CD8+ TILlow was not an independent prognostic factor. The 22C3 and E1L3N clones showed a high concordance rate (kappa value, 0.799). BRAF mutation status was not correlated with PD-L1 expression. We suggest that evaluation of the combined status of PD-L1 and TIL might be useful to predict the survival of patients with melanoma.

16.
J Neurooncol ; 136(3): 453-461, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29147863

RESUMEN

The aim of this study was to determine the clinicopathological significance of programmed cell death ligand 1 (PD-L1) expression in glioblastoma (GBM). In a retrospective cohort of 115 consecutive patients with GBM, PD-L1 expression was determined using immunohistochemistry (IHC). Membranous and fibrillary PD-L1 staining of any intensity in > 5% neoplastic cells and tumour infiltrating immune cells (TIIs) was considered positive staining. In addition, isocitrate dehydrogenase-1 (IDH-1) (R132H) expression and cluster of differentiation 3 (CD3)-positive T-cell infiltration were investigated using IHC. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation assay and fluorescence in situ hybridization (FISH) for the assessment of 1p/19q deletion were performed. Expression of PD-L1 in tumour cells and TIIs was found in 37 (32.2%) and 6 (5.2%) patients, respectively. Kaplan-Meier analysis indicated that PD-L1 expression in tumour cells was significantly associated with poor overall survival (OS) (P = 0.017), though multivariate Cox analysis did not confirm this association (hazard ratio 1.204; P = 0.615). PD-L1 expression in TIIs did not correlate with the patient prognosis (P = 0.545). In addition, MGMT methylation and IDH-1 (R132H) expression were associated with a better prognosis (P < 0.001 and P = 0.024, respectively). The expression of PD-L1 was associated with CD3-positive T-cell infiltration (P < 0.001), and IDH-1 wild type status (P = 0.008). A deeper insight into PD-L1 expression could help to ensure the success of future immunotherapy in GBM. Our study suggested that PD-L1 target therapy might be beneficial for PD-L1-expressing GBM patients with a poor prognosis.


Asunto(s)
Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Metilación de ADN , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Estudios de Seguimiento , Glioblastoma/genética , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas , Estudios Retrospectivos , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...