RESUMO
Pancreatic carcinoma is an aggressive tumour with increasing incidence in both sexes worldwide. Early detection is, therefore, essential for patient management. A recent advancement involves the utilization of larger, thicker gauge needles, which enable the collection of core-type biopsies (FNB). Here, we investigated the role of fine needle aspiration and cytopathology in the diagnostic workflow of pancreatic lesions. A search query was designed to search for articles in the PubMed database comparing FNA and FNB for biopsy of pancreatic lesions, and detailed data were extracted from selected studies. Statistical analyses were performed using the R package meta version 6.2. Twenty-one studies made the final cut for data extraction. Overall, median age was 64.3 years (±6.1; 47.6-71.5), male: female proportion 53.9 (±11.3; 27.6-67.4), lesion size 3.1 cm (±0.5; 1.9-4.2 cm) and percentage of malignant cases 78.3% (±26.8; 2.1-100). FNA and FNB diagnostic yield was 85.8% (±10.3; 70.0-100.0) and 89.2% (±7.7; 70.0-98.6), respectively. Average accuracy was 89.5% (±11.7; 63.0-100.0) for FNA and 90.8% (±7.1; 77.0-100.0) for FNB. Adverse effects rate was 1.0% (±1.3; 0-4.3) for FNA and 2.2% (±4.4; 0-16.1) for FNB. None of the selected variables had a significant statistical difference between both methods. FNA and FNB perform similarly for diagnostic material acquisition in pancreatic lesions. The best outcome comes from the association of both techniques, emphasizing the value of combining cytological and histological morphology for the most accurate analysis.
Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Neoplasias Pancreáticas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Biópsia com Agulha de Grande CalibreRESUMO
BACKGROUND: Physiological maternal stress response, such as imbalance in the glucocorticoid pathway and immune system seems to be mediated by DNA methylation (DNAm) and might translate intrauterine stress exposures into phenotypic changes in a sex-specific manner. DNAm in specific sites can also predict newborn gestational age and gestational age acceleration (GAA). GAA occurs when the predicted biological age is higher than the chronological age. In adults, poor health outcomes related to this deviance are well documented and raise questions for the interpretation and prediction in early stages of life. Boys seem to be more vulnerable to intrauterine stress exposure than girls; however, the mechanisms of adaptive sex-specific responses are still unclear. We hypothesize that intrauterine stress exposure is associated with GAA and could be different in boys and girls if inflammatory or glucocorticoid pathways exposure is considered. RESULTS: Using the Western Region Birth Cohort (ROC-São Paulo, Brazil) (n = 83), we calculated DNAm age and GAA from cord blood samples. Two epigenetic risk scores were calculated as an indirect proxy for low-grade inflammation (i-ePGS) and for glucocorticoid exposure (GES). Multivariate linear regression models were applied to investigate associations of GAA with prenatal exposures. The i-ePGS and GES were included in different models with the same co-variates considering sex interactions. The first multivariate model investigating inflammatory exposure (adj. R2 = 0.31, p = < 0.001) showed that GAA was positively associated with i-ePGS (CI, 0.26-113.87, p = 0.049) and negative pregnancy-related feelings (CI, 0.04-0.48 p = 0.019). No sex interaction was observed. The second model investigating glucocorticoid exposure (adj. R2 = 0.32, p = < 0.001) showed that the higher was the GAA was associated with a lower the lower was the GES in girls (CI, 0.04-2.55, p = 0.044). In both models, maternal self-reported mental disorder was negatively associated with GAA. CONCLUSION: Prenatal epigenetic score of exposure to low-grade inflammatory was a predictor of GAA for both sexes. Glucocorticoid epigenetic score seems to be more important to GAA in girls. This study supports the evidence of sex-specificity in stress response, suggesting the glucocorticoid as a possible pathway adopted by girls to accelerate the maturation in an adverse condition.
Assuntos
Metilação de DNA , Glucocorticoides , Adulto , Feminino , Masculino , Recém-Nascido , Gravidez , Humanos , Idade Gestacional , Glucocorticoides/efeitos adversos , Brasil , Biomarcadores , Aceleração , Epigênese GenéticaRESUMO
The crosstalk between maternal stress exposure and fetal development may be mediated by epigenetic mechanisms, including DNA methylation (DNAm). To address this matter, we collect 32 cord blood samples from low-income Brazilian pregnant adolescents participants of a pilot randomized clinical intervention study (ClinicalTrials.gov, Identifier: NCT02807818). We hypothesized that the association between the intervention and infant neurodevelopmental outcomes at 12 months of age would be mediated by DNAm. First, we searched genome methylation differences between cases and controls using different approaches, as well as differences in age acceleration (AA), represented by the difference of methylation age and birth age. According to an adjusted p-value ≤ 0.05 we identified 3090 differentially methylated positions- CpG sites (DMPs), 21 differentially methylated regions (DMRs) and one comethylated module weakly preserved between groups. The intervention group presented a smaller AA compared to the control group (p = 0.025). A logistic regression controlled by sex and with gestational age indicated a coefficient of -0.35 towards intervention group (p = 0.016) considering AA. A higher cognitive domain score from Bayley III scale was observed in the intervention group at 12 months of age. Then, we performed a potential causal mediation analysis selecting only DMPs highly associated with the cognitive domain (adj. R2 > 0.4), DMRs and CpGs of hub genes from the weakly preserved comethylated module and epigenetic clock as raw values. DMPs in STXBP6, and PF4 DMR, mediated the association between the maternal intervention and the cognitive domain at 12 months of age. In conclusion, DNAm in different sites and regions mediated the association between intervention and cognitive outcome.
Assuntos
Metilação de DNA , Epigênese Genética , Adolescente , Cognição , Epigenômica , Feminino , Sangue Fetal/metabolismo , Humanos , Exposição Materna , GravidezRESUMO
Indoleamine 2,3-dioxygenase (IDO) is associated with the progression of many types of tumors, including melanoma. However, there is limited information about IDO modulation on tumor cell itself and the effect of BRAF inhibitor (BRAFi) treatment and resistance. Herein, IDO expression was analyzed in different stages of melanoma development and progression linked to BRAFi resistance. IDO expression was increased in primary and metastatic melanomas from patients' biopsies, especially in the immune cells infiltrate. Using a bioinformatics approach, we also identified an increase in the IDO mRNA in the vertical growth and metastatic phases of melanoma. Using in silico analyses, we found that IDO mRNA was increased in BRAFi resistance. In an in vitro model, IDO expression and activity induced by interferon-gamma (IFNγ) in sensitive melanoma cells was decreased by BRAFi treatment. However, cells that became resistant to BRAFi presented random IDO expression levels. Also, we identified that treatment with the IDO inhibitor, 1-methyltryptophan (1-MT), was able to reduce clonogenicity for parental and BRAFi-resistant cells. In conclusion, our results support the hypothesis that the decreased IDO expression in tumor cells is one of the many additional outcomes contributing to the therapeutic effects of BRAFi. Still, the IDO production changeability by the BRAFi-resistant cells reiterates the complexity of the response arising from resistance, making it not possible, at this stage, to associate IDO expression in tumor cells with resistance. On the other hand, the maintenance of 1-MT off-target effect endorses its use as an adjuvant treatment of melanoma that has become BRAFi-resistant.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Vemurafenib/farmacologia , Linhagem Celular Tumoral , Bases de Dados Genéticas , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Melanoma/enzimologia , Melanoma/genética , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Triptofano/análogos & derivados , Triptofano/farmacologiaRESUMO
NRAS-mutations arise in 15-20% of all melanomas and are associated with aggressive disease and poor prognosis. Besides, the treatment for NRAS-mutant melanoma are not very efficient and is currently limited to immune checkpoints inhibitors or aggressive chemotherapy. 4-nerolidylcathecol (4-NC), a natural product extracted from Pothomorphe umbellata, induces apoptosis in melanoma cells by ROS production, DNA damage and increased p53 expression, in addition to inhibiting invasion in reconstructed skin. Moreover, 4-NC showed cytotoxicity in BRAF/MEKi-resistant and naive melanoma cells by Endoplasmic Reticulum (ER) stress induction in vitro. We evaluated the in vivo efficacy and the systemic toxicity of 4-NC in a NRAS-mutant melanoma model. 4-NC was able to significantly suppress tumor growth 4-fold compared to controls. Cleaved PARP and p53 expression were increased indicating cell death. As a proof of concept, MMP-2 and MMP-14 gene expression were decreased, demonstrating a possible role of 4-NC in melanoma invasion inhibition. Toxicological analysis indicated minor changes in the liver and bone marrow, but this toxicity was very mild when compared to other proteasome inhibitors and ER stress inductors already described. Our data indicate that 4-NC can counteract melanoma growth in vivo with minor adverse effects, suggesting further investigation as a potential NRAS-mutant melanoma treatment.
Assuntos
Antineoplásicos/farmacologia , Catecóis/farmacologia , GTP Fosfo-Hidrolases/genética , Melanoma/patologia , Proteínas de Membrana/genética , Mutação , Neoplasias Cutâneas/patologia , Animais , Antineoplásicos/toxicidade , Catecóis/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Melanoma/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Cutâneas/genética , Testes de Toxicidade Subaguda , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Cachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro-environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro-environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients. METHODS: 74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components. RESULTS: Higher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte-macrophage colony-stimulating factor, interferon-α, and interleukin (IL)-8 was observed in the tumour and serum of cachectic cancer patients in comparison with weight-stable counterparts. Also, IL-8 was positively correlated with weight loss in cachectic patients (P = 0.04; r = 0.627). Immunohistochemistry staining showed intense collagen deposition (P = 0.0006) and increased presence of α-smooth muscle actin (P < 0.0001) in tumours of cachectic cancer patients, characterizing fibrosis. In addition, higher transforming growth factor (TGF)-ß1, TGF-ß2, and TGF-ß3 expression (P = 0.003, P = 0.05, and P = 0.047, respectively) was found in the tumour of cachectic patients, parallel to p38 mitogen-activated protein kinase alteration. Hypoxia-inducible factor-1α mRNA content was significantly increased in the tumour of cachectic patients, when compared with weight-stable group (P = 0.005). CONCLUSIONS: Our results demonstrate TGF-ß pathway activation in the tumour in cachexia, through the (non-canonical) mitogen-activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF-ß-induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). We speculate that these changes may affect tumour aggressiveness and present consequences in peripheral organs.
Assuntos
Caquexia/etiologia , Caquexia/metabolismo , Neoplasias/complicações , Neoplasias/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Idoso , Biomarcadores , Biópsia , Composição Corporal , Índice de Massa Corporal , Caquexia/patologia , Células Cultivadas , Citocinas/metabolismo , Feminino , Fibroblastos , Fibrose , Expressão Gênica , Humanos , Hipóxia , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Estresse Oxidativo , Microambiente TumoralRESUMO
Esophageal infection by Candida spp. is a common opportunistic entity in immunocompromised hosts; however, systemic fungal dissemination due to perforation or transmural necrosis, also known as necrotizing Candida esophagitis (NCE), is rare. We report the case of a 61-year-old male patient with diagnosed ankylosing spondylitis, severe arteriosclerosis, and vasculitis under immunosuppressive therapy who presented NCE with fungal and bacterial septicemia diagnosed at autopsy. Necrotizing esophagitis is a rare manifestation of Candida infection, which may be a final complication in severely ill patients. Unfortunately, it may be underdiagnosed, and we call attention to this devastating complication in patients with leukocytoclastic cutaneous vasculitis and ankylosing spondylitis.
RESUMO
Multidrug resistance-associated protein 2 (MRP2) is a multi-specific organic anion transporter predominantly expressed in the canalicular membrane of hepatocytes, epithelial cells from gallbladder and apical membranes of proximal tubular kidney epithelium whereas multidrug resistance-associated protein 3 (MRP3) is present in the basolateral membrane of hepatocytes and cholangiocytes. This study aims to detect the expression of these transporters in hepatocellular carcinoma (HCC) and in cholangiocarcinoma (CC), searching for evidences for future studies on differential diagnosis and on clinical essays. The immunohistochemical reactivity (IHC) of these transporters was assessed in tissue microarrays of 80 HCC and 56 CC cases using monoclonal antibodies and compared with anatomopathological (AP) variables. The positivity of MRP2 was observed in 92.3% of HCC and in 96.3% of CC. The detection of high MRP2 expression in HCC was not significantly different (p > 0.05) according to the size, number of nodules architectural pattern and growth pattern of HCC and CC. Regarding histological grades, 22/22 well moderately differentiated HCC versus 50/56 poorly differentiated HCC were positive for MRP2. A trend for lower expression in poor differentiation HCC was found. And 50/50 well/moderately differentiated CC versus 2/4 poorly/undifferentiated CC were positive for MRP2. This result showed a reduced expression (p = 0,0004) in poorly differentiated CC. MRP3 positivity was observed in 18.8% of HCC and was not significantly different according to AP parameters. MRP3 was expressed in 44.5% CC, with a trend for lower expression in less differentiated CC and significantly lower rates in the ductular histological subtype (p = 0.023). The high expression of MRP2 in HCC and in CC is conserved regardless most of the anatomopathological parameters, except for a trend of lower expression in less differentiated HCC and CC. The observation of lower MRP3 expression in less differentiated CC and, especially, in the histological subtype with expression of hepatic progenitor cell phenotypes leads to future opportunities to evaluate the expression of this marker in cholangiocarcinomas.
Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Colangiocarcinoma/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/patologia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , PrognósticoRESUMO
BACKGROUND AND AIMS: Early gastric cancer (EGC) is known to present a low rate of lymph node metastases (LNMs). Gastrectomy with D2 lymphadenectomy is usually curative for EGC. Endoscopic submucosal dissection (ESD) is a well-accepted treatment modality for lesions that meet the classic criteria: those mucosal differentiated adenocarcinoma measuring 20 mm or less, without ulceration. Expanded criteria for ESD have been proposed based on a null LNM rate from large gastrectomy series from Japan. Patients with LNM have been reported in Western centers, heightening the need for validation of expanded criteria. Our aim was to assess the risk of LNM in gastrectomy specimens of patients with EGC who met the expanded criteria for ESD. METHODS: We conducted an evaluation of gastrectomy specimens including LNM staging of patients submitted to gastrectomy for EGC in a 39-year retrospective cohort. RESULTS: A total of 389 surgical specimens were included. From them, 135 fulfilled criteria for endoscopic resection. None of the 31 patients with classic criteria had LNM. From the 104 patients with expanded criteria, 3 had LNM (n = 104 [2.9%], 95% confidence interval, .7%-8.6%), all of them with undifferentiated tumors without ulceration, measuring less than 20 mm. CONCLUSIONS: There is a small risk of LNM in EGC when expanded criteria for ESD are met. Refinement of the expanded criteria for the risk of LNM may be desirable in a Brazilian cohort. Meanwhile, the decision to complement the endoscopic treatment with gastrectomy will have to take into consideration the individual risk of perioperative morbidity and mortality.