RESUMO
Human papillomavirus (HPV) is a major causative factor of head and neck squamous cell carcinoma (HNSCC), and the incidence of HPV- associated HNSCC is increasing. The role of tumor microenvironment in viral infection and metastasis needs to be explored further. We studied the molecular characteristics of primary tumors (PTs) and lymph node metastatic tumors (LNMTs) by stratifying them based on their HPV status. Eight samples for single-cell RNA profiling and six samples for spatial transcriptomics (ST), composed of matched primary tumors (PT) and lymph node metastases (LNMT), were collected from both HPV- negative (HPV- ) and HPV-positive (HPV+ ) patients. Using the 10x Genomics Visium platform, integrative analyses with single-cell RNA sequencing were performed. Intracellular and intercellular alterations were analyzed, and the findings were confirmed using experimental validation and publicly available data set. The HPV+ tissues were composed of a substantial amount of lymphoid cells regardless of the presence or absence of metastasis, whereas the HPV- tissue exhibited remarkable changes in the number of macrophages and plasma cells, particularly in the LNMT. From both single-cell RNA and ST data set, we discovered a central gene, pyruvate kinase muscle isoform 1/2 (PKM2), which is closely associated with the stemness of cancer stem cell-like populations in LNMT of HPV- tissue. The consistent expression was observed in HPV- HNSCC cell line and the knockdown of PKM2 weakened spheroid formation ability. Furthermore, we found an ectopic lymphoid structure morphology and clinical effects of the structure in ST slide of the HPV+ patients and verified their presence in tumor tissue using immunohistochemistry. Finally, the ephrin-A (EPHA2) pathway was detected as important signals in angiogenesis for HPV- patients from single-cell RNA and ST profiles, and knockdown of EPHA2 declined the cell migration. Our study described the distinct cellular composition and molecular alterations in primary and metastatic sites in HNSCC patients based on their HPV status. These results provide insights into HNSCC biology in the context of HPV infection and its potential clinical implications.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas/patologia , Papillomavirus Humano , Papillomaviridae/genética , Neoplasias de Cabeça e Pescoço/genética , Perfilação da Expressão Gênica/métodos , RNA , Microambiente Tumoral/genéticaRESUMO
Diffuse large B-cell lymphoma (DLBCL) is a prevalent and aggressive non-Hodgkin's lymphoma, and 40% of patients succumb to death. Despite numerous clinical trials aimed at developing treatment strategies beyond the conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, there have been no positive results thus far. Although the selective BCL2 inhibitor venetoclax has shown remarkable efficacy in chronic lymphocytic leukemia, its therapeutic effect in DLBCL was limited. We hypothesized that the limited therapeutic effect of venetoclax in DLBCL may be attributed to the complex expression and interactions of BCL2 family members, including BCL2. Therefore, we aimed to comprehensively analyze the expression patterns of BCL2 family members in DLBCL. We analyzed 157 patients with de novo DLBCL diagnosed at Asan Medical Center and Ajou University Hospital. The mRNA expression levels of BCL2 family members were quantified using the NanoString technology. BCL2 family members showed distinct heterogeneous expression patterns both intra- and inter-patient. Using unsupervised hierarchical cluster analysis, we were able to classify patients with similar BCL2 family expression pattern and select groups with clear prognostic features, C1 and C6. In the group with the best prognosis, C1, the expression of pro-apoptotic and pro-apoptotic BH3-only group gene expressions were increased, while anti-apoptotic group expression was significantly increased in both C1 and C6. Based on this, we generated the BCL2 signature score using the expression of pro-apoptotic genes BOK and BCL2L15, and anti-apoptotic gene BCL2. The BCL2 signature score 0 had the best prognosis, score 1/2 had intermediate prognosis, and score 3 had the worst prognosis (EFS, p = 0.0054; OS, p = 0.0011). Multivariate analysis, including COO and IPI, showed that increase in the BCL2 signature score was significantly associated with poor prognosis for EFS, independent of COO and IPI. The BCL2 signature score we proposed in this study provides information on BCL2 family deregulation based on the equilibrium of pro-versus anti-apoptotic BCL2 family, which can aid in the development of new treatment strategies for DLBCL in the future.
Assuntos
Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-bcl-2 , Humanos , Anticorpos Monoclonais Murinos/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Rituximab/uso terapêutico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Ciclofosfamida/uso terapêutico , Vincristina/uso terapêutico , Prednisona/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Overexpression of the BCL2 protein has been reported as a poor prognostic factor for diffuse large B-cell lymphoma (DLBCL). However, there are currently no standardized criteria for evaluating BCL2 protein expression. We aimed to evaluate the prognostic value of BCL2 expression determined by immunohistochemistry (IHC), incorporating both the staining intensity and proportion, in patients with de novo DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment. We defined tumors with BCL2 expression in nearly all tumor cells with a uniformly strong intensity by IHC as BCL2 super-expressor. The BCL2 super-expressors (n = 35) showed significantly worse event-free survival (EFS; HR, 1.903; 95% CI, 1.159-3.126, P = 0.011) and overall survival (OS; HR, 2.467; 95% CI, 1.474-4.127, P = 0.001) compared with the non-BCL2 super-expressors (n = 234) independent of the international prognostic index (IPI), cell of origin (COO), and double expressor status in the training set (n = 269). The adverse prognostic impact of BCL2 super-expression was confirmed in the validation set (n = 195). When the survival outcomes were evaluated in the entire cohort (n = 464), BCL2 super-expressor group was significantly associated with inferior EFS and OS regardless of IPI, COO, MYC expression, and stages. BCL2 super-expressors had genetic aberrations enriched in the NOTCH and TP53 signaling pathways. This study suggests that the BCL2 super-expressor characterizes a distinct subset of DLBCL with a poor prognosis and warrants further investigation as a target population for BCL-2 inhibitors.
Assuntos
Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-bcl-2 , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Prednisona/uso terapêutico , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Rituximab/uso terapêutico , Vincristina/uso terapêuticoRESUMO
BACKGROUND: Recent clinical studies on immune checkpoint (IC) inhibitors in the context of advanced gastric cancer (AGC) have failed to show significant survival benefits but have suggested the possible role of IC inhibitors in anti-AGC immunity. Considering the low efficacy of targeted drugs in AGC, there is an urgent need for the discovery of new targets for the development of immunotherapeutics and prognostic markers for patient selection. This study aimed to investigate the expression of a new IC molecule, V-set Ig domain-containing 4 (VSIG4), and its clinical significance in AGC and other major cancers. METHODS: We analyzed the expression of VSIG4 and its correlation with survival in various carcinomas, including 882 surgically resected samples from patients with stage II-III AGC (two academic hospitals). RESULTS: VSIG4 positivity in AGC was significantly associated with overall survival (OS; Hazard ratio (HR) = 2.661, 95% confidence interval [CI] = 2.012-3.519, P < 0.001) and event-free survival (HR = 2.8, 95% CI = 2.18-3.72, P < 0.001). These findings were successfully validated in independent cohorts. VSIG4 expression was also significantly correlated with low intratumoral CD8 + T-cell infiltration (CD8i) (P = 0.029) and high Foxp3 + /CD8i ratio (P = 0.026), which is consistent with the previously reported immunological function of VSIG4. However, VSIG4 expression was not associated with survival in other cancers (colon, P = 0.459; lung, P = 0.275; kidney, P = 0.121; breast, P = 0.147). CONCLUSION: Our results suggest that VSIG4 is an independent prognostic factor in AGC and also implies that VSIG4 is a second-tier IC molecule in AGC, thus, providing an important basis for the development of gastric cancer-specific immunotherapeutics.
Assuntos
Receptores de Complemento/metabolismo , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Biomarcadores Tumorais/imunologia , Feminino , Mucosa Gástrica/imunologia , Mucosa Gástrica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Taxa de SobrevidaRESUMO
Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas (EBV+-DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV+-DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV+-DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV+-DLBLs revealed enrichment of mutations in Rho pathway genes, including RHPN2, and Rho pathway transcriptomic activation. Targeting the Rho pathway using a Rho-associated protein kinase (ROCK) inhibitor, fasudil, markedly decreased tumor growth in EBV+-DLBL patient-derived xenograft (PDX) models. Thus, alterations in the Rho pathway appear to contribute to EBV-induced lymphomagenesis in immunosuppressed environments.
Assuntos
Adenocarcinoma/metabolismo , Transformação Celular Viral , Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/virologia , Animais , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Camundongos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia , Proteínas rho de Ligação ao GTP/genéticaRESUMO
BACKGROUND: Clinical sequencing data should be shared in order to achieve the sufficient scale and diversity required to provide strong evidence for improving patient care. A distributed research network allows researchers to share this evidence rather than the patient-level data across centers, thereby avoiding privacy issues. The Observational Medical Outcomes Partnership (OMOP) common data model (CDM) used in distributed research networks has low coverage of sequencing data and does not reflect the latest trends of precision medicine. OBJECTIVE: The aim of this study was to develop and evaluate the feasibility of a genomic CDM (G-CDM), as an extension of the OMOP-CDM, for application of genomic data in clinical practice. METHODS: Existing genomic data models and sequencing reports were reviewed to extend the OMOP-CDM to cover genomic data. The Human Genome Organisation Gene Nomenclature Committee and Human Genome Variation Society nomenclature were adopted to standardize the terminology in the model. Sequencing data of 114 and 1060 patients with lung cancer were obtained from the Ajou University School of Medicine database of Ajou University Hospital and The Cancer Genome Atlas, respectively, which were transformed to a format appropriate for the G-CDM. The data were compared with respect to gene name, variant type, and actionable mutations. RESULTS: The G-CDM was extended into four tables linked to tables of the OMOP-CDM. Upon comparison with The Cancer Genome Atlas data, a clinically actionable mutation, p.Leu858Arg, in the EGFR gene was 6.64 times more frequent in the Ajou University School of Medicine database, while the p.Gly12Xaa mutation in the KRAS gene was 2.02 times more frequent in The Cancer Genome Atlas dataset. The data-exploring tool GeneProfiler was further developed to conduct descriptive analyses automatically using the G-CDM, which provides the proportions of genes, variant types, and actionable mutations. GeneProfiler also allows for querying the specific gene name and Human Genome Variation Society nomenclature to calculate the proportion of patients with a given mutation. CONCLUSIONS: We developed the G-CDM for effective integration of genomic data with standardized clinical data, allowing for data sharing across institutes. The feasibility of the G-CDM was validated by assessing the differences in data characteristics between two different genomic databases through the proposed data-exploring tool GeneProfiler. The G-CDM may facilitate analyses of interoperating clinical and genomic datasets across multiple institutions, minimizing privacy issues and enabling researchers to better understand the characteristics of patients and promote personalized medicine in clinical practice.
Assuntos
Bases de Dados Factuais/normas , Genômica/métodos , Medicina de Precisão/métodos , Humanos , Estudos RetrospectivosRESUMO
Previous studies have examined various immune evasion strategies of human cytomegalovirus (HCMV) to gain understanding of its pathogenesis. Although the mechanism that underlies immunocyte destruction near HCMV-infected lesions has yet to be established, it is here shown that substances produced by HCMV-infected cells induce death in several types of immunocytes, but not in fibroblasts or astrocytomas. These substances contain HCMV proteins and were termed HCMV-associated insoluble substance (HCMVAIS). The mechanism by which HCMVAIS induces cell death was characterized to improve understanding the death of immunocytes near HCMV-infected lesions. HCMVAIS were found to trigger production of intracellular nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species (ROS), resulting in cell death, this effect being reversed following treatment with ROS inhibitors. Cell death was not induced in splenocytes from NOX-2 knockout mice. It was hypothesized that DNA damage induced by oxidative stress initiates poly ADP-ribose polymerase-1 (PARP-1)-mediated cell death, or parthanatos. HCMVAIS-induced cell death is accompanied by PARP-1 activation in a caspase-independent manner, nuclear translocation of apoptosis-inducing factor (AIF), and DNA fragmentation, which are typical features of parthanatos. Treatment with an AIF inhibitor decreased the rate of HCMVAIS-induced cell death, this being confirmed by hematoxylin and eosin staining; cell death in most HCMV-positive foci in serial section samples of a large intestine with HCMV infection was TUNEL-positive, cleaved caspase 3-negative and CD45-positive. Taken together, these data suggest that HCMV inhibits local immune responses via direct killing of immunocytes near HCMV-infected cells through ROS-induced parthanatos by HCMVAIS.
Assuntos
Citomegalovirus/metabolismo , Espécies Reativas de Oxigênio , Proteínas Virais/farmacologia , Animais , Fator de Indução de Apoptose , Linfócitos T CD4-Positivos/efeitos dos fármacos , Caspase 3 , Morte Celular/efeitos dos fármacos , Linhagem Celular , Citomegalovirus/patogenicidade , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Evasão da Resposta Imune , Intestino Grosso/patologia , Intestino Grosso/virologia , Células Jurkat/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Poli(ADP-Ribose) Polimerases/farmacologia , Células THP-1/efeitos dos fármacosRESUMO
BACKGROUND: Primary cutaneous mucinous carcinoma (PCMC) is a rare epithelial tumor with unclear histogenesis. METHODS: We evaluated the immunohistochemical expression of the estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) in six cases of PCMC. The immunoreactivity of adipophilin and gross cystic disease fluid protein (GCDFP)-15 was investigated to determine the origin of the tumor. RESULTS: The study included five males and one female aged 50 to 69 years who presented with a cutaneous mass in the face. Immunoreactivity for ER, PR, and AR was observed in all cases, and all cases were negative for adipophilin but positive for GCDFP-15. CONCLUSIONS: This report is the first to show AR expression in PCMC. All of followed cases manifested indolent clinical course, and the prognostic significance of hormone receptors in PCMC remains unclear. The negative immunoreactivity of PCMC for adipophilin and positivity for GCDFP-15 suggests a more likely relationship to apocrine than to sebaceous glands.
Assuntos
Adenocarcinoma Mucinoso/metabolismo , Proteínas de Transporte/biossíntese , Neoplasias Faciais/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/biossíntese , Proteínas de Neoplasias/biossíntese , Perilipina-2/biossíntese , Receptores de Esteroides/biossíntese , Neoplasias Cutâneas/metabolismo , Adenocarcinoma Mucinoso/patologia , Idoso , Neoplasias Faciais/patologia , Feminino , Humanos , Masculino , Proteínas de Membrana Transportadoras , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologiaRESUMO
OBJECTIVES: Mantle cell lymphoma (MCL) has a heterogeneous clinical course. Although most cases show a poor prognosis, a minority has an indolent course. It is difficult to identify indolent MCL cases prospectively. T-cell leukemia/lymphoma protein 1 (TCL1) is expressed by several B-cell lymphomas, including MCL. This study examined the expression of TCL1 and its prognostic relevance for MCL. METHODS: Clinical data for 162 patients with MCL were collected. Of these, 144 cases with available tissues for tissue microarray construction and immunostaining were included in the analysis. TCL1 staining was quantified using the Nuclear Quant application with Pannoramic™ Viewer v. 1.14. High TCL1 expression was defined as moderate to strong nuclear and/or cytoplasmic staining in 40% or more of the cells. RESULTS: High TCL1 expression was observed in 39 of 144 samples (27.1%). Patients with low TCL1 expression were more likely to present with blastoid/pleomorphic morphology (P = 0.010). Low TCL1 expression was associated with significantly shorter overall survival (OS, P = 0.006). Multivariate analysis identified low TCL1 expression (P = 0.003), high-risk MIPI (P = 0.027), and anemia (P = 0.018) as adverse prognostic factors. CONCLUSIONS: Our study suggests that TCL1 expression profile may have a role in the prediction of overall outcome in patient with MCL and call for prospective studies.
Assuntos
Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/mortalidade , Proteínas Proto-Oncogênicas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais , Terapia Combinada , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas/genética , Curva ROC , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND/AIMS: Autophagy is crucial for the survival and function of plasma cells including protection from toxic misfolded immunoglobulin and proper energy metabolism. Multiple myeloma (MM) is an indolent but eventually fatal neoplasm of plasma cells. Autophagy may play a critical role in the survival of MM cells and their response to chemotherapeutic agents. In this study, we correlated the expression of autophagy-related proteins with the prognosis of MM. METHODS: In this retrospective cohort study, we examined the expression of the autophagic markers BECLIN 1 and microtubule-associated protein light chain 3 (LC3) in 89 cases of MM biopsied from 2001 to 2004 at the Asan Medical Center. The association of the expression scores of these markers with clinical outcomes was assessed. RESULTS: Patients with strong immunoreactivity to BECLIN 1 or LC3 had a significantly better overall survival (OS) than patients with negative to moderate immunoreactivity (p = 0.036 and 0.018, respectively). This was also true for disease-specific survival (DSS; p = 0.051 and 0.043, respectively). In addition, LC3 immunostaining remained an independent factor impacting OS (p = 0.028) and DSS (p = 0.020) after multivariate analysis. CONCLUSIONS: The results of this study suggest that higher immunoreactivity for autophagic markers in MM is associated with superior patient survival.
Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Autofagia , Biomarcadores Tumorais/biossíntese , Proteínas de Membrana/biossíntese , Proteínas Associadas aos Microtúbulos/biossíntese , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Proteínas de Neoplasias/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína Beclina-1 , Intervalo Livre de Doença , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
In Epstein-Barr virus (EBV)-infected gastric carcinoma, EBV-encoded BARF1 has been hypothesized to function as an oncogene. To evaluate cellular changes induced by BARF1, we isolated the full-length BARF1 gene from gastric carcinoma cells that were naturally infected with EBV and transfected BARF1 into EBV-negative gastric carcinoma cells. BARF1 protein was primarily secreted into culture supernatant and only marginally detectable within cells. Compared with gastric carcinoma cells containing empty vector, BARF1-expressing gastric carcinoma cells exhibited increased cell proliferation (P < 0.05). There were no significant differences in apoptosis, invasion, or migration between BARF1-expressing gastric carcinoma cells and empty vector-transfected cells. BARF1-expressing gastric carcinoma cells demonstrated increased nuclear expression of nuclear factor kappa B (NF-κB) RelA protein and increased NF-κB-dependent cyclin D1. The expression of p21(WAF1) was diminished by BARF1 transfection and increased by NF-κB inhibition. Proliferation of naturally EBV-infected gastric carcinoma cells was suppressed by BARF1 small interfering RNA (siRNA) (P < 0.05). Immunohistochemical analysis of 120 human gastric carcinoma tissues demonstrated increased expression of cyclin D1 and reduced expression of p21(WAF1) in EBV-positive samples versus EBV-negative gastric carcinomas (P < 0.05). In conclusion, the secreted BARF1 may stimulate proliferation of EBV-infected gastric carcinoma cells via upregulation of NF-κB/cyclin D1 and reduction of the cell cycle inhibitor p21(WAF1), thereby facilitating EBV-induced cancer progression.
Assuntos
Proliferação de Células , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/patogenicidade , NF-kappa B/metabolismo , Neoplasias Gástricas/patologia , Proteínas Virais/metabolismo , Apoptose , Western Blotting , Adesão Celular , Movimento Celular , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , NF-kappa B/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/virologia , Células Tumorais Cultivadas , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/genéticaAssuntos
Neoplasias Duodenais/diagnóstico , Mucosa Intestinal/patologia , Linfoma de Células T/diagnóstico , Idoso , Constrição Patológica , Duodenopatias/etiologia , Neoplasias Duodenais/complicações , Neoplasias Duodenais/patologia , Humanos , Linfoma de Células T/complicações , Linfoma de Células T/patologia , MasculinoRESUMO
BACKGROUND: Little is known about gastric neoplasms arising from hyperplastic polyps (HPs). OBJECTIVE: To investigate the risk factors associated with neoplasms within HPs and to evaluate the role of alterations of the p16-cyclin D1-pRb pathway in the malignant transformation of HPs. DESIGN: Retrospective, case-control study. SETTING: Tertiary-care center. PATIENTS: Between May 1995 and January 2011, a total of 809 HPs >1 cm were investigated. Associated neoplasms were present in 30 HPs (case group); 30 HPs without neoplasms were selected as a control group. INTERVENTIONS: Gastric polypectomy. MAIN OUTCOME MEASUREMENTS: The risk factors associated with neoplasms within HPs and immunohistochemical expression of p16, cyclin D1, p53, and Ki-67 between case and control groups. RESULTS: Of the 809 HPs, 15 had associated dysplasia, and 15 had carcinoma. Multivariate analysis showed that neoplasm was associated with patient age (odds ratio [OR] 1.159; 95% confidence interval [CI], 1.243-2.044; P < .001), polyp size (OR 1.103; 95% CI, 1.055-1.152; P < .001), and polyp lobulation (OR 4.549; 95% CI, 1.759-11.0766; P < .001) but not with location, multiplicity, intestinal metaplasia, growth pattern, or Helicobacter pylori infection. Loss of p16 expression and high Ki-67 expression were observed in dysplastic areas of HPs compared with the control group (p16 = 14.3% vs 60%; P = .001, Ki-67 = 60.7% vs 36.7%; P < .001). However, no significant differences were found in nondysplastic areas in both groups. LIMITATIONS: Single-center, retrospective study. CONCLUSION: HPs >1 cm may indicate the presence of neoplasms. Loss of p16 and high Ki-67 expression may be markers of HP-associated dysplasia.
Assuntos
Carcinoma/metabolismo , Pólipos/metabolismo , Gastropatias/metabolismo , Neoplasias Gástricas/metabolismo , Fatores Etários , Idoso , Carcinoma/complicações , Carcinoma/patologia , Estudos de Casos e Controles , Ciclina D1/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina , Feminino , Infecções por Helicobacter/complicações , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Pólipos/complicações , Pólipos/patologia , Estudos Retrospectivos , Fatores de Risco , Gastropatias/complicações , Gastropatias/patologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/patologia , Carga Tumoral , Proteína Supressora de Tumor p53/metabolismoRESUMO
Despite the vital importance of monitoring the progression of nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), an efficient imaging modality that is readily available at hospitals is currently lacking. Here, a new magnetic-resonance-imaging (MRI)-based imaging modality is presented that allows for efficient and longitudinal monitoring of NAFLD and NASH progression. The imaging modality uses manganese-ion (Mn2+)-chelated bilirubin nanoparticles (Mn@BRNPs) as a reactive-oxygen-species (ROS)-responsive MRI imaging probe. Longitudinal T1-weighted MR imaging of NASH model mice is performed after injecting Mn@BRNPs intravenously. The MR signal enhancement in the liver relative to muscle gradually increases up to 8 weeks of NASH progression, but decreases significantly as NASH progresses to the cirrhosis-like stage at weeks 10 and 12. A new dual input pseudo-three-compartment model is developed to provide information on NASH stage with a single MRI scan. It is also demonstrated that the ROS-responsive Mn@BRNPs can be used to monitor the efficacy of potential anti-NASH drugs with conventional MRI. The findings suggest that the ROS-responsive Mn@BRNPs have the potential to serve as an efficient MRI contrast for monitoring NASH progression and its transition to the cirrhosis-like stage.
Assuntos
Bilirrubina , Progressão da Doença , Cirrose Hepática , Imageamento por Ressonância Magnética , Nanopartículas , Hepatopatia Gordurosa não Alcoólica , Espécies Reativas de Oxigênio , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Animais , Imageamento por Ressonância Magnética/métodos , Camundongos , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Cirrose Hepática/diagnóstico por imagem , Meios de Contraste/química , Manganês/química , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Fígado/metabolismo , Modelos Animais de DoençasRESUMO
This study focused on a novel strategy that combines deep learning and radiomics to predict epidermal growth factor receptor (EGFR) mutations in patients with non-small cell lung cancer (NSCLC) using computed tomography (CT). A total of 1280 patients with NSCLC who underwent contrast-enhanced CT scans and EGFR mutation testing before treatment were selected for the final study. Regions of interest were segmented from the CT images to extract radiomics features and obtain tumor images. These tumor images were input into a convolutional neural network model to extract 512 image features, which were combined with radiographic features and clinical data to predict the EGFR mutation. The generalization performance of the model was evaluated using external institutional data. The internal and external datasets contained 324 and 130 EGFR mutants, respectively. Sex, height, weight, smoking history, and clinical stage were significantly different between the EGFR-mutant patient groups. The EGFR mutations were predicted by combining the radiomics and clinical features, and an external validation dataset yielded an area under the curve (AUC) value of 0.7038. The model utilized 1280 tumor images, radiomics features, and clinical characteristics as input data and exhibited an AUC of approximately 0.81 and 0.78 during the primary cohort and external validation, respectively. These results indicate the feasibility of integrating radiomics analysis with deep learning for predicting EGFR mutations. CT-image-based genetic testing is a simple EGFR mutation prediction method, which can improve the prognosis of NSCLC patients and help establish personalized treatment strategies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Aprendizado Profundo , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Mutação , RadiômicaRESUMO
Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.
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Although little is known about the behavior of engineered nanomaterials after exposure to terrestrial areas, recent studies indicate that silver nanoparticles (AgNPs) can perturb the soil environment due to their biocidal and catalytic properties. The fundamental evaluation of the environmental fate of AgNPs would be a significant step toward a comprehensive understanding of the harmful effects of such particles on ecosystems. Therefore, from an eco-toxicological perspective, the estimation of AgNP behavior in soil should be investigated. Among the various environmental characteristics, the deposition of nanoparticles in the soil constitute is a critical step in their migration into surface or groundwater and interaction with organisms, which is determined by the stability of aqueous dispersions in a soil micro-environment. In the present study, we observed the aggregation and deposition of AgNPs to natural soil surfaces by comparing the partitioning of AgNPs in a soil/water interface with that of Ag+ ion. Both AgNPs and Ag+ ion were selectively quantified by means of inductively coupled plasma (ICP) spectrometry and an ion-selective electrode (ISE). We interpreted the partitioning of AgNPs and Ag+ ion using the Freundlich isotherm and the findings indicate that AgNPs with reduced dispersion stability in a soil micro-environment were aggregated and deposited on the surface of natural soil. This study provides a fundamental basis for understanding the deposition of AgNPs, which will enable their accumulation and mobility in a soil environment to be predicted.
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Differential diagnosis of anaplastic thyroid carcinoma/poorly differentiated thyroid carcinoma (ATC/PDTC) from differentiated thyroid carcinoma (DTC) is crucial in patients with large thyroid malignancies. This study creates a predictive model using radiomics feature analysis to differentiate ATC/PDTC from DTC. We compared the clinicoradiological characteristics and radiomics features extracted from a volume of interest on contrast-enhanced computed tomography (CT) between the groups. Estimations of variable importance were performed via modeling using the random forest quantile classifier. The diagnostic performance of the model with radiomics features alone had the area under the receiver operating characteristic (AUROC) curve value of 0.883. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 81.7%, 93.3%, 97.7%, 64.5%, and 84.6%, respectively, for the differential diagnosis of ATC/PDTC and DTC. The model with both radiomics and clinicoradiological information showed the AUROC of 0.908, with sensitivity, specificity, PPV, NPV, and accuracy of 82.9%, 97.6%, 99.2%, 67.1%, and 86.5% respectively. Distant metastasis, moment, shape, age, and gray-level size zone matrix features were the most useful factors for differential diagnosis. Therefore, we concluded that a radiomics approach based on contrast-enhanced CT features can potentially differentiate ATC/PDTC from DTC in patients with large thyroid malignancies.
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Adenocarcinoma , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Projetos Piloto , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Carcinoma Anaplásico da Tireoide/diagnóstico por imagem , Carcinoma Anaplásico da Tireoide/patologia , Tomografia Computadorizada por Raios X , Estudos RetrospectivosRESUMO
Deep learning has been widely used to analyze digitized hematoxylin and eosin (H&E)-stained histopathology whole slide images. Automated cancer segmentation using deep learning can be used to diagnose malignancy and to find novel morphological patterns to predict molecular subtypes. To train pixel-wise cancer segmentation models, manual annotation from pathologists is generally a bottleneck due to its time-consuming nature. In this paper, we propose Deep Interactive Learning with a pretrained segmentation model from a different cancer type to reduce manual annotation time. Instead of annotating all pixels from cancer and non-cancer regions on giga-pixel whole slide images, an iterative process of annotating mislabeled regions from a segmentation model and training/finetuning the model with the additional annotation can reduce the time. Especially, employing a pretrained segmentation model can further reduce the time than starting annotation from scratch. We trained an accurate ovarian cancer segmentation model with a pretrained breast segmentation model by 3.5 hours of manual annotation which achieved intersection-over-union of 0.74, recall of 0.86, and precision of 0.84. With automatically extracted high-grade serous ovarian cancer patches, we attempted to train an additional classification deep learning model to predict BRCA mutation. The segmentation model and code have been released at https://github.com/MSKCC-Computational-Pathology/DMMN-ovary.