RESUMO
INTRODUCTION: In this study, we aimed to evaluate the predictive value of circulating lymphocyte subsets and inflammatory indexes in response to neoadjuvant chemoradiotherapy (NCRT) in patients with rectal mucinous adenocarcinomas (MACs). METHODS: Rectal MAC patients who underwent NCRT and curative resection at Fujian Medical University Union Hospital's Department of Colorectal Surgery between 2016 and 2020 were included in the study. Patients were categorized into good and poor response groups based on their pathological response to NCRT. An independent risk factor-based nomogram model was constructed by utilizing multivariate logistic regression analysis. Additionally, the extreme gradient boosting (XGB) algorithm was applied to build a machine learning (ML)-based predictive model. Feature importance was quantified using the Shapley additive explanations method. RESULTS: Out of the 283 participants involved in this research, 190 (67.1%) experienced an unfavorable outcome. To identify the independent risk factors, logistic regression analysis was performed, considering variables such as tumor length, pretreatment clinical T stage, PNI, and Th/Tc ratio. Subsequently, a nomogram model was constructed, achieving a C-index of 0.756. The ML model exhibited higher prediction accuracy than the nomogram model, achieving an AUROC of 0.824 in the training set and 0.762 in the tuning set. The top five important parameters of the ML model were identified as the Th/Tc ratio, neutrophil to lymphocyte, Th lymphocytes, Gross type, and T lymphocytes. CONCLUSION: Radiochemotherapy sensitivity is markedly influenced by systemic inflammation and lymphocyte-mediated immune responses in rectal MAC patients. Our ML model integrating clinical characteristics, circulating lymphocyte subsets, and inflammatory indexes is a potential assessment tool that can provide a reference for individualized treatment for rectal MAC patients.
Assuntos
Adenocarcinoma Mucinoso , Aprendizado de Máquina , Terapia Neoadjuvante , Nomogramas , Neoplasias Retais , Humanos , Masculino , Neoplasias Retais/terapia , Neoplasias Retais/patologia , Neoplasias Retais/imunologia , Feminino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/imunologia , Subpopulações de Linfócitos/imunologia , Idoso , Valor Preditivo dos Testes , Estudos Retrospectivos , Resultado do Tratamento , Quimiorradioterapia/métodos , Fatores de Risco , Adulto , Inflamação , Quimiorradioterapia Adjuvante/métodosRESUMO
Ovarian cancers include several disease subtypes and patients often present with advanced metastatic disease and a poor prognosis. New biomarkers for early diagnosis and targeted therapy are, therefore, urgently required. This study uses antibodies produced locally in tumor-draining lymph nodes (ASC probes) of individual ovarian cancer patients to screen two separate protein microarray platforms and identify cognate tumor antigens. The resulting antigen profiles were unique for each individual cancer patient and were used to generate a 50-antigen custom microarray. Serum from a separate cohort of ovarian cancer patients encompassing four disease subtypes was screened on the custom array and we identified 28.8% of all ovarian cancers, with a higher sensitivity for mucinous (50.0%) and serous (40.0%) subtypes. Combining local and circulating antibodies with high-density protein microarrays can identify novel, patient-specific tumor-associated antigens that may have diagnostic, prognostic or therapeutic uses in ovarian cancer.
Assuntos
Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma Mucinoso/diagnóstico , Antígenos de Neoplasias/imunologia , Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Cistadenocarcinoma Seroso/diagnóstico , Neoplasias Ovarianas/diagnóstico , Adenocarcinoma de Células Claras/sangue , Adenocarcinoma de Células Claras/imunologia , Adenocarcinoma Mucinoso/sangue , Adenocarcinoma Mucinoso/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/sangue , Autoanticorpos/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Estudos de Casos e Controles , Estudos de Coortes , Cistadenocarcinoma Seroso/sangue , Cistadenocarcinoma Seroso/imunologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/imunologia , Prognóstico , Análise Serial de Proteínas , Adulto JovemRESUMO
BACKGROUND: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600EBRAF-mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting. METHODS: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests. RESULTS: Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001). CONCLUSIONS: Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.
Assuntos
Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Linfócitos do Interstício Tumoral/imunologia , Mutação , Sinaptofisina/genética , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/imunologia , Adenocarcinoma Mucinoso/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
INTRODUCTION: Determining the risk of malignancy in a pancreatic cyst (PC) is a clinical and diagnostic challenge. Monoclonal antibody (mAb) Das-1 test was shown to have high sensitivity, specificity, and accuracy in detecting high-risk (HR) cysts. Das-1 mAb test detects HR mucinous cysts with high-grade dysplasia (HGD), invasive carcinoma, and/or intestinal-type epithelium. Correlation of mAb Das-1 testing of PC fluids with cytomorphologic findings has not been evaluated. MATERIALS AND METHODS: We correlated cytology with mAb Das-1 test results and resection histology in 26 PCs. There were 18 intraductal papillary mucinous neoplasms (IPMN), 1 intraductal oncocytic papillary neoplasm (IOPN), 4 mucinous cystic neoplasms (MCN), 2 serous cystadenomas, and 1 cystic pancreatic neuroendocrine tumor (PanNET). HR cysts included cysts with high-grade atypia on cytology or HGD on histology, invasive carcinoma, IOPNs, and cystic PanNETs. Intestinal type IPMNs were also HR cysts on histology. RESULTS: In 17 cases (65.38%), cytology and mAb Das-1 test correlated with histology. There were 2 (7.69%) mAb Das-1 test negative HR PCs diagnosed by cytology. Five (19.23%) mAb Das-1 test positive HR PCs had mucin only or cells with low-grade dysplasia on cytology. Two mAb Das-1 test positive HR PCs had nondiagnostic cytology. HR IOPN and cystic PanNET were not detected by mAb Das-1 test. CONCLUSION: The mAb Das-1 is a sensitive and specific biomarker for detecting HR mucinous PCs. Adding cytology to mAb Das-1 testing improves the sensitivity for the detection of nonmucinous HR PC. Together, cytology with mAb Das-1 testing is more accurate than either one alone.
Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Anticorpos Monoclonais/imunologia , Anticorpos/imunologia , Cistadenoma Seroso/diagnóstico , Citodiagnóstico/métodos , Tumores Neuroendócrinos/diagnóstico , Cisto Pancreático/diagnóstico , Neoplasias Intraductais Pancreáticas/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Adenocarcinoma Mucinoso/imunologia , Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/imunologia , Líquido Cístico/imunologia , Cistadenoma Seroso/imunologia , Cistadenoma Seroso/patologia , Confiabilidade dos Dados , Humanos , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/patologia , Cisto Pancreático/imunologia , Cisto Pancreático/patologia , Neoplasias Intraductais Pancreáticas/imunologia , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Período Pré-Operatório , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: The heat shock protein 90 (HSP90s) family is composed of molecular chaperones composed of four isoforms in humans, which has been widely reported as unregulated in various kinds of cancers. Nevertheless, the role of each HSP90s isoform in prognosis and immune infiltration in distinct subtypes of breast cancer (BRAC) remains unclear. METHODS: Public online databases including the Oncomine, UALCAN, Kaplan-Meier Plotter, Tumor IMmune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), GeneMANIA, and Database for Annotation, Visualization, and Integrated Discovery (DAVID) were integrated to perform bioinformatic analyses and to explore the possible associations among HSP90s gene expression, prognosis, and immune infiltration in BRAC. RESULTS: The mRNA expression of all HSP90s members was elevated in distinct clinical stages and subtypes of BRAC, compared with the normal breast tissue (P < 0.05). Overexpressed HSP90AA1 was associated with poor prognosis, particularly, both short overall survival (OS) and release-free survival (RFS) in Basal-like BRAC patients; overexpressed HSP90AB1 and HSP90B1 were both associated with poor RFS in Luminal A BRAC patients, while overexpressed TRAP1 was associated with favorable RFS in Luminal A BRAC patients. Moreover, HSP90s gene expression in BRAC showed correlations with the infiltration of CD8+ T cells, neutrophils, macrophages, and dendritic cells (DCs), as well as the activation of tumor-associated macrophages (TAMs), DCs, and CD4+ helper T (Th) cells. The underlying mechanisms of HSP90s modulating tumor-infiltrating immune cells (TIICs) might be related with their functions in antigen processing and presentation, major histocompatibility complex (MHC) binding, and assisting client proteins. CONCLUSION: This study demonstrated that HSP90s family genes were overexpressed and might be serve as prognostic biomarkers in subtypes of BRAC. It might be a novel breakthrough point of BRAC treatment to regulate immune infiltration in BRAC microenvironment for more effective anticancer immunity through pharmacological intervention of HSP90s.
Assuntos
Adenocarcinoma Mucinoso/genética , Neoplasias da Mama/genética , Carcinoma Ductal/genética , Carcinoma Lobular/genética , Proteínas de Choque Térmico HSP90/genética , Glicoproteínas de Membrana/genética , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/imunologia , Adenocarcinoma Mucinoso/patologia , Atlas como Assunto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Ductal/diagnóstico , Carcinoma Ductal/imunologia , Carcinoma Ductal/patologia , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Movimento Celular , Biologia Computacional/métodos , Bases de Dados Genéticas , Células Dendríticas/imunologia , Células Dendríticas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP90/imunologia , Humanos , Glicoproteínas de Membrana/imunologia , Anotação de Sequência Molecular , Invasividade Neoplásica , Prognóstico , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/patologiaRESUMO
OBJECTIVE: The aim of the study was to clarify the diagnostic impact of measuring serum anti-p53 antibody (S-p53Ab) in predicting the histological grades of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. METHODS: We compared the measured values and positive prevalence of S-p53Ab across the different histological grades of 111 resected IPMN cases. We also evaluated the TP53 alterations using immunohistochemistry and next-generation sequencing. RESULTS: Serum anti-p53 antibody were detected in 6 of 111 cases, all of their histological grades were high-grade dysplasia (HGD) and invasive carcinoma (INV). Positive prevalence of S-p53Ab was higher in cases with INV (4/35 cases, 11.4%) than those with HGD (2/38 cases, 5.3%), whereas S-p53Abs were undetectable in cases with low-grade dysplasia. Measured S-p53Ab values were not correlated with either carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA 19-9). In 4 of 6 S-p53Ab-positive cases, the TP53 alterations-somatic pathogenic mutations or aberrant immunoreactivity-were identified in their IPMN lesions. A combination assay of S-p53Ab, CEA, and CA 19-9 revealed a 38.4% sensitivity and 81.6% specificity for predicting HGD/INV. CONCLUSIONS: Serum anti-p53 antibody can serve as a surrogate marker for TP53 alterations and help predict the presence of HGD/INV in cases with IPMN, in combination with CEA and CA 19-9.
Assuntos
Adenocarcinoma Mucinoso/sangue , Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Papilar/sangue , Neoplasias Pancreáticas/sangue , Proteína Supressora de Tumor p53/imunologia , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Antígeno CA-19-9/análise , Antígeno Carcinoembrionário/análise , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/imunologia , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/imunologia , Feminino , Proteínas Ligadas por GPI/análise , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/imunologia , Sensibilidade e Especificidade , Proteína Supressora de Tumor p53/genéticaRESUMO
Mucinous colorectal adenocarcinoma (CRC) is conventionally defined by extracellular mucin comprising >50% of the tumour area, while tumours with ≤50% mucin are designated as having a mucinous component. However, these definitions are largely arbitrary and comparisons of clinico-molecular features and outcomes by proportion of mucinous component are limited. A cohort of 1643 patients with stage II/III cancer was examined for tumour mucinous component, DNA mismatch repair (MMR) status, BRAF mutation and tumour infiltrating lymphocytes (TILs). Tumours with ≤50% mucinous component exhibited similar characteristics as mucinous tumours, including association with female gender, proximal location, high grade, TIL-high, defective MMR (dMMR) and BRAF mutation. Proportion of mucinous component did not stratify disease-free survival (DFS). In univariate analysis dMMR status, but not histological grade, stratified survival for mucinous and mucinous component tumours; however, in multivariate analysis dMMR status was not an independent predictor. BRAF mutation prognostic value depended on mucinous differentiation and MMR status, with poor prognosis limited to non-mucinous pMMR tumours (HR 2.61, 95% CI 1.69-4.03; p < 0.001). TIL status was a strong independent predictor of DFS in mucinous/mucinous component tumours (HR 0.40, 95% CI 0.23-0.67; p < 0.001), and a superior predictor of prognosis compared with histological grade, MMR and BRAF mutation. Mucinous component and mucinous stage II/III CRCs exhibit clinico-molecular resemblances, with histological grade and BRAF mutation lacking prognostic value. Prognosis for these tumours was instead strongly associated with TIL status, with the most favourable outcomes in TIL-high dMMR tumours, whilst TIL-low tumours had poor outcomes irrespective of MMR status.
Assuntos
Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Linfócitos do Interstício Tumoral/patologia , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Reparo de Erro de Pareamento de DNA , Intervalo Livre de Doença , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Aim: To explore the impact of preoperative the albumin-to-globulin ratio (AGR) and the prognostic nutritional index (PNI) on prognosis in rectal mucinous adenocarcinoma (MAC). Methods: A total of 128 patients were included. Results: According to the X-tile analysis, cutoff values of AGR and PNI were 1.1 and 43.8. Preoperative AGR (p = 0.041), preoperative PNI (p = 0.036) and pTNM stage (p = 0.003) were independently associated with overall survival in rectal MAC patients. Distance from the anal verge (p = 0.005), preoperative AGR (p = 0.021), preoperative PNI (p = 0.007) and pTNM stage (p < 0.001) were significantly associated with disease-free survival in rectal MAC patients. Nomograms for overall survival and disease-free survival were developed (C-index: 0.739 and 0.764). Conclusion: Preoperative AGR and PNI can act as effective predictors for survival for rectal MAC patients.
Assuntos
Adenocarcinoma Mucinoso/imunologia , Adenocarcinoma Mucinoso/mortalidade , Imunidade , Estado Nutricional , Neoplasias Retais/imunologia , Neoplasias Retais/mortalidade , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Avaliação Nutricional , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Retais/patologia , Albumina Sérica Humana , Soroglobulinas , Análise de SobrevidaRESUMO
AIMS: Testis Expressed 19 (TEX19) is one of cancer/testis antigens identified in recent years and is related to the oncogenesis and progress of several cancers. This study aimed to reveal the role of TEX19 in ovarian cancer (OC) and searched for potential candidate epitope peptides of TEX19 to facilitate clinical application. MAIN METHODS: TEX19 levels were evaluated by immunohistochemistry (IHC) in 98 human ovarian tissue samples. The correlation of TEX19 levels with patients' clinicopathological features was assessed. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis were utilized to detect TEX19 levels in ovarian cell lines and TEX19-deficient cells. The level of TEX19 in OVCAR-3 and A2780 was knocked down by small interfering RNA (siRNA), and loss-of-function assays were used to determine the biological effects of TEX19 on the proliferation, migration, and invasion of OC cells. Subsequently, candidate epitope peptides from TEX19 were predicted and verified by the IEDB database, pepsite2 website, MOE software, and T2 cell binding assay. KEY FINDINGS: TEX19 was significantly upregulated in OC which correlated to higher TNM stage, lymph node involvement, and invasiveness. Knockdown of TEX19 inhibited proliferation, migration, and invasion of OC cells. Additionally, we screened four peptides derived from TEX19 and found TL to be the dominant peptide with the greatest affinity with HLA-A*0201. SIGNIFICANCE: Our data indicated a cancer-promoting effect of TEX19 in OC and demonstrated that TL could be a potential candidate for an anti-tumor epitope vaccine of OC, suggesting that TEX19 is a promising biomarker and immunotherapeutic target for OC.
Assuntos
Adenocarcinoma de Células Claras/secundário , Adenocarcinoma Mucinoso/secundário , Cistadenocarcinoma Seroso/secundário , Neoplasias do Endométrio/secundário , Epitopos/imunologia , Neoplasias Ovarianas/patologia , Proteínas de Ligação a RNA/imunologia , Proteínas de Ligação a RNA/metabolismo , Adenocarcinoma de Células Claras/imunologia , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma Mucinoso/imunologia , Adenocarcinoma Mucinoso/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Cistadenocarcinoma Seroso/imunologia , Cistadenocarcinoma Seroso/metabolismo , Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto JovemRESUMO
BACKGROUND: Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment. Recently, a new global transcriptomic immune classification of solid tumours has identified six immune subtypes (ISs) (C1-C6). Our aim was to specifically characterise ISs in colorectal cancer (CRC) and assess their interplay with the consensus molecular subtypes (CMSs). METHODS: Clinical and molecular information, including CMSs and ISs, were obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, differential gene expression and gene set enrichment analysis were performed to characterise ISs in the global CRC population by using CMSs. RESULTS: Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), whereas all C6 TGF-ß dominant cases belonged to CMS4 (2.3%). Prognostic relevance of ISs in CRC substantially differed from that reported for the global TCGA, and ISs had a greater ability to stratify the prognosis of CRC patients than CMS classification. C2 had higher densities of CD8, CD4 activated, follicular helper T cells, regulatory T cells and neutrophils and the highest M1/M2 polarisation. C2 had a heightened activation of pathways related to the immune system, apoptosis and DNA repair, mTOR signalling and oxidative phosphorylation, whereas C1 was more dependent of metabolic pathways. CONCLUSIONS: The correlation of IS and CMS allows a more precise categorisation of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in CRC patients.
Assuntos
Adenocarcinoma Mucinoso/classificação , Adenocarcinoma/classificação , Neoplasias Colorretais/classificação , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/imunologia , Adenocarcinoma Mucinoso/metabolismo , Idoso , Linfócitos T CD8-Positivos , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal/genética , Feminino , Genes MHC Classe I/genética , Humanos , Inflamação/imunologia , Interferon gama/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Macrófagos/imunologia , Masculino , Instabilidade de Microssatélites , Monócitos/imunologia , Monócitos/metabolismo , Neovascularização Patológica , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Fator de Crescimento Transformador beta/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Via de Sinalização Wnt/genética , Cicatrização/genética , Cicatrização/imunologiaRESUMO
BACKGROUND/AIM: The presence of ascites in ovarian cancer patients is considered a negative prognostic factor. The underlying mechanisms are not clearly understood. MATERIALS AND METHODS: The amount of ascites was evaluated, preferably, using diffusion-weighted MRI at primary diagnosis in a retrospective cohort of 214 women with ovarian cancer, in an ordinal manner (amount of ascites: none, limited, moderate, abundant). In a prospective cohort comprising 45 women with ovarian cancer, IL-10 (interleukin), VEGF (vascular endothelial growth factor), TGF-ß (transforming growth factor) and CCL-2 [chemokine (C-C) motif ligand 2] were measured at diagnosis (and at interval debulking, when available). RESULTS: Gradually increasing amounts of ascites were correlated significantly, even after correction for FIGO stage, with reduced survival (p<0.0001) and stronger immunosuppression (IL10 and VEGF). Neoadjuvant chemotherapy reduced immunosuppression, which was observed as a reduction in CCL-2, IL-10 and VEGF. CONCLUSION: The amount of ascites is an independent predictor of survival and correlates with increased immunosuppression.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ascite/mortalidade , Terapia de Imunossupressão/mortalidade , Terapia Neoadjuvante/efeitos adversos , Neoplasias Ovarianas/mortalidade , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/imunologia , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/imunologia , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ascite/etiologia , Ascite/patologia , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/imunologia , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Intestinal-type adenocarcinoma of the primary salivary glands is extremely rare. So far, only 11 cases of primary intestinal-type adenocarcinoma of the oral cavity and major salivary glands have been reported. Two of those tumors arose in the floor of mouth, 7 in the tongue, and 2 in the major salivary glands. However, it has remained unclear whether these tumors are derived from mature salivary glands, and primary intestinal-type adenocarcinoma of the buccal mucosa has not been reported previously. Here, we present the first documented case of primary intestinal-type adenocarcinoma arising in a minor salivary gland of the buccal mucosa. Histopathologically, the tumor resembled a well-differentiated or mucinous colonic adenocarcinoma. Immunohistochemically, the tumor cells were diffusely positive for AE1/AE3, CAM5.2, CK7, SATB2, ß-catenin, p53, Ki-67, MUC2, and MUC5 AC. CK14 and CK20 were positive in some of the tumor cells. CDX2, CA19-9, SP-A, TTF-1, PSA, SMA, p63, and cyclin D1 were negative in the tumor cells. The tumor in the present case may have originated from salivary gland duct epithelium that underwent transformation to phenotypic intestinal-type epithelium. In this very rare case of primary intestinal-type adenocarcinoma of the buccal mucosa, we considered diagnostic markers that could be indicative of mature salivary gland origin.
Assuntos
Adenocarcinoma Mucinoso , Adenocarcinoma , Proteínas de Ligação à Região de Interação com a Matriz , Neoplasias Bucais , Adenocarcinoma Mucinoso/imunologia , Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais , Humanos , Imuno-Histoquímica , Mucosa Bucal/patologia , Neoplasias Bucais/imunologia , Neoplasias Bucais/patologia , Fatores de TranscriçãoRESUMO
The role of mast cells (MCs) in colorectal cancer (CRC) progression was controversial. Thus, our study was designed to evaluate the prognostic value of MCs as well as their correlation with immune microenvironment. A retrospective cohort of CRC patients of stages I-IV was enrolled in our study. Consecutive patients (854) were divided into training set (427 patients) and validation set (427 patients) randomly. The findings were further validated in a GEO cohort, GSE39582 (556 patients). The mast cell density (MCD) was measured by immunohistochemical staining of tryptase or by CIBERSORT algorithm. Low MCD predicted prolonged overall survival (OS) in training and validation set. Moreover, MCD was identified as an independent prognostic indicator in both sets. Better stratification for CRC prognosis can be achieved by building a MCD based nomogram. The prognostic role of MCD was further validated in GSE39582. In addition, MCD predicted improved survival in stages II and III CRC patients receiving adjuvant chemotherapy (ACT). Multiple immune pathways were enriched in low MCD group while cytokines/chemokines promoting anti-tumor immunity were highly expressed in such group. Furthermore, MCD was negatively correlated with CD8+ T cells infiltration. In conclusion, MCD was identified as an independent prognostic factor, as well as a potential biomarker for ACT benefit in stages II and III CRC. Better stratification of CRC prognosis could be achieved by building a MCD based nomogram. Moreover, immunoactivation in low MCD tumors may contributed to improved prognosis.
Assuntos
Adenocarcinoma Mucinoso/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/imunologia , Mastócitos/imunologia , Nomogramas , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/metabolismo , Algoritmos , Contagem de Células , Quimioterapia Adjuvante , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Gastric carcinoma management requires adjustments answering their genetic and morphologic heterogeneity. We aim to assess the expression and significance of a myriad of biomarkers (p53, MLH1, MSH2, PMS2, MSH6, Epstein-Barr encoding region-RNA, c-erbB2, E-cadherin, CEA, chromogranin, Ki-67, CDX2, presenilin-1, cathepsin E, MUC5AC, cyclin-dependent kinase 1) in 117 gastric carcinomas, which we have morphologically subclassified with a simple algorithm. Immunohistochemical stains were applied to 3 tissue microarrays of primary gastric carcinomas (n=117) obtained from resection specimens of untreated patients. These cases represented the morphologic subgroups that emerged from a reclassification attempt carried out according to the predominant (>50%) morphologic component they contained (adenocarcinoma, diffuse infiltrative carcinoma, mucinous carcinoma) and "mixed" carcinoma if none predominated. Cases with unusual morphology were assigned to a "special subtypes" group ("rare" tumors). Correlation of overall survival and staining patterns was carried out. Adenocarcinomas comprised 43.6% (n=51), diffuse infiltrative carcinomas 28.2% (n=33), mucinous carcinomas 6% (n=7), mixed carcinomas 6%, and "rare/other" carcinomas 16.2% (n=19) of the 117 muscle-invasive carcinoma cases. High tumor stage was associated with worse overall survival at multivariate analysis (P=0.000, log-rank). Higher cathepsin E and cyclin-dependent kinase 1 expression was associated with worse overall survival on univariate analysis (log-rank; P=0.050 and 0.001, respectively). Mismatch repair defects were seen in adenocarcinomas and "rare" tumors with MLH1 silencing. These above-mentioned points can lead to the differentiation of metabolic and phenotypic features per gastric carcinoma subtype and may help design targeted approaches.
Assuntos
Adenocarcinoma Mucinoso , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica/imunologia , Proteínas de Neoplasias , Neoplasias Gástricas , Adenocarcinoma Mucinoso/imunologia , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/imunologia , Estadiamento de Neoplasias , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologiaAssuntos
Adenocarcinoma Mucinoso/patologia , Quimiorradioterapia/métodos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/cirurgia , Cuidados Pré-Operatórios/métodos , Adenocarcinoma Mucinoso/imunologia , Colectomia/métodos , Colo Ascendente/diagnóstico por imagem , Colo Ascendente/patologia , Colo Ascendente/cirurgia , Neoplasias do Colo/patologia , Neoplasias do Colo/radioterapia , Duodeno/cirurgia , Fluordesoxiglucose F18/administração & dosagem , Humanos , Jejuno/cirurgia , Linfonodos/patologia , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/normas , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Ureter/cirurgiaRESUMO
PURPOSE: The aim of this study was to evaluate the influence of ovarian cancer cell lysates isolated from type I or type II ovarian cancer (OC) on the phenotype of monocyte-derived dendritic cells (Mo-DCs) and the cytokine profile. We also determined whether the Mo-DCs and tumor microenvironment, reflected by peritoneal fluid (PF) from type I or II ovarian cancer, could promote regulatory T cell (Tregs) differentiation from naive CD4+ lymphocytes in vitro. RESULTS: Our results show a significant role of the ovarian cancer microenvironment reflected by PF from type I or II OC in the inhibition of the DC differentiation process. Interestingly, the percentage of cells co-expressing CD45 and CD14 antigens in the cultures stimulated with PF from both type I and type II OC was higher than in the control. Furthermore, the percentage of cells expressing CD1a, i.e., a marker of immature DCs, was significantly reduced in the cultures stimulated with PF from type I and type II OC. The results obtained show that ovarian cancer type II lysates induce differentiation of monocytes into macrophage-like cells with a CD1a+/HLA-DR+/CD83- phenotype and significantly higher CD86/HLA-DR expression. We show that ovarian cancer type II Mo-DCs are able to prevent an immune response by release of IL-10, whereas OC type I Mo-DCs can promote the generation of Tregs. CONCLUSIONS: We demonstrate that each type of ovarian cancer can induce a unique phenotype of DCs and differentiation of Tregs, both associated with immune-suppressive function, which may be an obstacle while developing effective anticancer dendritic cell vaccination.
Assuntos
Diferenciação Celular , Células Dendríticas/patologia , Monócitos/patologia , Neoplasias Ovarianas/patologia , Linfócitos T Reguladores/patologia , Microambiente Tumoral , Adenocarcinoma Mucinoso/imunologia , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Cistadenocarcinoma Seroso/imunologia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Interleucina-10/metabolismo , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Fenótipo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Tumorais Cultivadas , Adulto JovemRESUMO
OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon subtype of epithelial ovarian cancers, and the pathogenesis is still poorly understood because of its rarity. We conducted a gene set-based analysis to investigate the pathogenesis of MOC by integrating microarray gene expression datasets based on the regularity of functions defined by gene ontology or canonical pathway databases. MATERIALS AND METHODS: Forty-five pairs of MOC and normal ovarian tissue sample gene expression profiles were downloaded from the National Center for Biotechnology Information Gene Expression Omnibus database. The gene expression profiles were converted to the gene set regularity indexes by measuring the change of gene expression ordering in a gene set. Then the pathogenesis of MOC was investigated with the differences of function regularity with the gene set regularity indexes between the MOC and normal control samples. RESULTS: The informativeness of the gene set regularity indexes was sufficient for machine learning to accurately recognize and classify the functional regulation patterns with an accuracy of 99.44%. The statistical analysis revealed that the GTPase regulators and receptor tyrosine kinase erbB-2 (ERBB2) were the most important aberrations; the exploratory factor analysis revealed phosphoinositide 3-kinase-activating kinase, G-protein coupled receptor pathway, oxidoreductase activity, immune response, peptidase activity, regulation of translation, and transport and channel activity were also involved in the pathogenesis of MOC. CONCLUSION: Investigating the pathogenesis of MOC with the functionome provided a comprehensive view of the deregulated functions of this disease. In addition to GTPase regulators and ERBB2, a plenty of deregulated functions such as phosphoinositide 3-kinase, G-protein coupled receptor pathway, and immune response also participated in the interaction network of MOC pathogenesis.
Assuntos
Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/metabolismo , Perfilação da Expressão Gênica/métodos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Transcriptoma , Adenocarcinoma Mucinoso/imunologia , Bases de Dados Genéticas , Análise Fatorial , Feminino , Genes erbB-2 , Humanos , Aprendizado de Máquina , Redes e Vias Metabólicas/genética , Análise em Microsséries , Neoplasias Ovarianas/imunologia , Ovário , Transdução de Sinais/genéticaRESUMO
OBJECTIVES: Concurrent intraductal papillary-mucinous neoplasm (IPMN) and autoimmune pancreatitis (AIP) was observed in a patient (index case) at our institution. Cases of coincidental IPMN and type 1 AIP and concurrent ductal adenocarcinoma (PDAC) and AIP have been previously reported. In this study we evaluate the hypothesis that IPMN elicits an IgG4 response. METHODS: Twenty-one pancreases (including the index case) with IPMN resected at our institution were studied. H&E stained slides were reviewed and blocks of peritumoral pancreas were immunostained with IgG4 to look for IgG4-positive plasma cells. RESULTS: We found evidence of variable IgG4 overexpression in 4/21 (19%) of IPMN. These included the index case and three others without stigmata of AIP. CONCLUSION: A small subset of pancreatic neoplasms including intraductal papillary-mucinous neoplasms (IPMN) is associated with an IgG4 autoimmune response that sometimes progresses to peritumoral type 1 AIP and less often to diffuse AIP and IgG4-related systemic disease.
Assuntos
Adenocarcinoma Mucinoso/patologia , Doenças Autoimunes/imunologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Papilar/patologia , Imunoglobulina G/sangue , Pancreatite/imunologia , Adenocarcinoma Mucinoso/complicações , Adenocarcinoma Mucinoso/imunologia , Doenças Autoimunes/patologia , Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/imunologia , Carcinoma Papilar/complicações , Carcinoma Papilar/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/complicações , Pancreatite/patologiaRESUMO
The loss of insulin-producing pancreatic ß-cells in Type 1 diabetes mellitus (DM) is presumably the result of a T cell-mediated process. In general, CD8+ T cells are the predominant lymphocytes in the insulitis lesions, and CD4+ T cell-dominant insulitis is very rare. We present a case of a 72-year-old woman presented with excessive thirst and a 3-month history of weight loss. She was in a state of ketosis, and her plasma glucose concentration and HbA1c value were elevated. Moreover, anti-islet autoantibodies were positive, thus acute-onset Type 1 DM was diagnosed. At the time of diagnosis, a tumour was detected in the pancreas; total pancreatectomy was carried out 2 months later. The pathological diagnosis was intraductal papillary mucinous adenoma. Immunohistochemical staining of a sample of non-tumorous pancreatic tissue revealed 13 insulitis lesions infiltrated by both CD4+ and CD8+ T cells, and interestingly there were more CD4+ T cells than CD8+ T cells in the lesions. Moreover, B cells and macrophages had also infiltrated the lesions, and these two cell frequencies were both positively correlated with CD4+ as well as CD8+ T cell frequencies. This was a rare case with acute-onset Type 1 DM characterized by CD4+ T cell-dominant insulitis. Proinflammatory cytokines that can promote ß-cell apoptosis or CD8+ T cell function are reported to be secreted from CD4+ T cells. Thus, together with B cells and macrophages, CD4+ T cell-associated immune responses may have, directly and/or indirectly, played a role in the pathogenesis of the Type 1 DM in this patient.
Assuntos
Adenocarcinoma Mucinoso/complicações , Linfócitos T CD4-Positivos/fisiologia , Carcinoma Intraductal não Infiltrante/complicações , Carcinoma Ductal Pancreático/complicações , Diabetes Mellitus Tipo 1/complicações , Ilhotas Pancreáticas/imunologia , Neoplasias Pancreáticas/complicações , Adenocarcinoma Mucinoso/imunologia , Idade de Início , Idoso , Autoanticorpos/sangue , Carcinoma Intraductal não Infiltrante/imunologia , Carcinoma Ductal Pancreático/imunologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Insulina/sangue , Insulina/deficiência , Neoplasias Pancreáticas/imunologiaRESUMO
Premalignant lesions for many cancers have been identified, and efforts are currently directed toward identification of antigens expressed on these lesions that would provide suitable targets for vaccines for cancer prevention. Intraductal papillary mucinous neoplasms (IPMNs) are premalignant pancreatic cysts of which a subset has the potential to progress to cancer. Currently, there are no validated predictive markers for progression to malignancy. We hypothesized that the presence or absence of immune surveillance of these lesions would be one such factor. Here we show that the tumor antigen MUC1, which is abnormally expressed on pancreatic cancer and is a target for cancer immunosurveillance, is also abnormally expressed on premalignant IPMN. We show that some IPMN patients make MUC1-specific IgG. Moreover, we show evidence of CD4 and CD8 T cell infiltration into IPMN areas of high dysplasia suggesting an ongoing immune response within the lesions. We also found, however, increased levels of circulating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in some IPMN patients as well as evidence of T cell exhaustion. Further studies correlating immunosurveillance or immunosuppression with IPMN progression to malignancy will help define the immune response as a biomarker of risk, leading potentially to a vaccine to boost spontaneous immunity and prevent progression to cancer.