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1.
Am J Gastroenterol ; 114(9): 1539-1549, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31306149

RESUMO

OBJECTIVES: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2). DISCUSSION: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.


Assuntos
Carcinoma Ductal Pancreático/genética , Cistadenoma Seroso/genética , Metilação de DNA/genética , Cisto Pancreático/genética , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Pancreáticas/genética , Lesões Pré-Cancerosas/genética , Idoso , Proteína Morfogenética Óssea 3/genética , Antígeno Carcinoembrionário/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/patologia , Líquido Cístico/metabolismo , Cistadenoma Seroso/diagnóstico , Cistadenoma Seroso/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Cisto Pancreático/diagnóstico , Cisto Pancreático/patologia , Neoplasias Intraductais Pancreáticas/diagnóstico , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Reação em Cadeia da Polimerase , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteínas com Domínio T/genética
2.
Pancreas ; 48(6): 749-758, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31206466

RESUMO

To evaluate the diagnostic accuracy of KRAS mutation in pancreatic cystic fluid and compare it with carcinoembryonic antigen and cytology, we identified studies with cyst fluid obtained by endoscopic ultrasound prior to surgery. We classified cysts as malignant, premalignant, and benign. A random-effects model was used for quantitative meta-analysis. Pooled sensitivities, specificities, and summary receiver operating characteristic curve analysis were conducted. We analyzed 16 studies, with 3429 patients, including 731 referred for surgery. Carcinoembryonic antigen was better for clinically significant cysts (premalignant and malignant) with sensitivity = 0.58 (95% confidence interval [CI], 0.53-0.65), specificity = 0.9 (95% CI, 0.76-0.97), and area under the curve (AUC) = 0.69. Cytology performed better in malignant cysts, with sensitivity = 0.37 (95% CI, 0.27-0.48), specificity = 0.96 (95% CI, 0.93-0.98), and AUC = 0.78. Isolated, KRAS mutation failed the diagnosis of malignant and significant cysts, with sensitivities = 0.43 (95% CI, 0.34-0.43) and 0.46 (95% CI, 0.42-0.51), specificities = 0.62 (95% CI, 0.56-0.68) and 0.97 (95% CI, 0.92-0.99), and AUCs = 0.56 and 0.53, respectively. Carcinoembryonic antigen and cytology are more accurate than KRAS. Additional studies are lacking to recommend KRAS as a single diagnostic test.


Assuntos
Líquido Cístico/metabolismo , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Cisto Pancreático/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/análise , Antígeno Carcinoembrionário/análise , Humanos , Cisto Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
3.
Pediatr Dev Pathol ; 22(4): 304-314, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31033383

RESUMO

INTRODUCTION: Chorionic cysts of the chorion laeve, fetal chorionic plate, septum, and free membranes have been associated with placental hypoxia, but they have no clear clinical significance. Although immunohistochemistry has identified fibronectin and collagen IV in cyst fluid, the contents have yet to be fully characterized. METHODS: Placental chorionic cysts (N = 10) were sampled by fluid extraction and hemotoxylin and eosin-stained sections. Amniotic fluid samples (N = 8) were obtained from pregnant women who had cytogenetic evaluation. The content of the cysts was tested for thrombogenicity using thromboelastography. The cyst content was tested by Luminex multiplex and ELISA assays and for known prothrombotic and proinflammatory factors. RESULTS: We identified cysts, especially those in the chorionic plate, adjacent to intervillous thrombi with apparent cyst rupture. Thromboelastography revealed a significantly shorter R time compared to whole blood control samples. Concentration of creatinine, α-fetoprotein, and surfactant D in the cyst fluid differed significantly from amniotic fluid. Cyst fluids had a significantly higher expression of all prothrombotic and some proinflammatory factors. DISCUSSION: Our data provide the first evidence that chorionic cyst fluid is prothrombotic and different from amniotic fluid. The association of ruptured cysts with adjacent thrombi and the prothrombotic properties of cyst fluid suggest a causal relationship; however, further studies are needed.


Assuntos
Doenças Placentárias/patologia , Placenta/patologia , Trombose/patologia , Líquido Amniótico/metabolismo , Córion/patologia , Líquido Cístico/metabolismo , Cistos/patologia , Feminino , Humanos , Gravidez , Tromboelastografia
5.
Genes Chromosomes Cancer ; 58(1): 3-11, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30230086

RESUMO

Approximately half of all pancreatic cysts are neoplastic, mainly comprising intraductal papillary mucinous neoplasms (IPMN), which can progress to invasive carcinoma. Current Fukuoka guidelines have limited sensitivity and specificity in predicting progression of asymptomatic pancreatic cysts. We present first results of the prospective ZYSTEUS biomarker study investigating (i) whether detection of driver mutations in IPMN by liquid biopsy is technically feasible, (ii) which compartment of IPMN is most suitable for analysis, and (iii) implications for clinical diagnostics. Twenty-two patients with clinical inclusion criteria were enrolled in ZYSTEUS. Fifteen cases underwent endoscopic ultrasound (EUS)-guided fine-needle aspiration and cytological diagnostics. Cellular and liquid fraction of the cysts of each case were separated and subjected to deep targeted next generation sequencing (NGS). Clinical parameters, imaging findings (EUS and MRI), and follow-up data were collected continuously. All IPMN cases (n = 12) showed at least one mutation in either KRAS (n = 11) or GNAS (n = 4). Three cases showed both KRAS and GNAS mutations. Six cases harbored multiple KRAS/GNAS mutations. In the three cases with pseudocysts, no KRAS or GNAS mutations were detected. DNA yields were higher and showed higher mutation diversity in the cellular fraction. In conclusion, mutation detection in pancreatic cyst fluid is technically feasible with more robust results in the cellular than in the liquid fraction. Current results suggest that, together with imaging, targeted sequencing supports discrimination of IPMN from pseudocysts. The prospective design of ZYSTEUS will provide insight into diagnostic value of NGS in preoperative risk stratification. Our data provide evidence for an oligoclonal nature of IPMN.


Assuntos
Biópsia por Agulha Fina , Cisto Pancreático/diagnóstico , Neoplasias Intraductais Pancreáticas/diagnóstico , Pseudocisto Pancreático/diagnóstico , Idoso , Biomarcadores Tumorais/genética , Cromograninas/genética , Líquido Cístico/metabolismo , Diagnóstico Diferencial , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Cisto Pancreático/metabolismo , Cisto Pancreático/patologia , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Intraductais Pancreáticas/metabolismo , Neoplasias Intraductais Pancreáticas/patologia , Pseudocisto Pancreático/patologia , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética , Ultrassonografia
6.
Am J Physiol Renal Physiol ; 316(1): F204-F213, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30403162

RESUMO

In autosomal dominant polycystic kidney disease (ADPKD) paracrine signaling molecules in cyst fluid can induce proliferation and cystogenesis of neighboring renal epithelial cells. However, the identity of this cyst-inducing factor is still unknown. The aim of this study was to identify paracrine signaling proteins in cyst fluid using a 3D in vitro cystogenesis assay. We collected cyst fluid from 15 ADPKD patients who underwent kidney or liver resection (55 cysts from 13 nephrectomies, 5 cysts from 2 liver resections). For each sample, the ability to induce proliferation and cyst formation was tested using the cystogenesis assay (RPTEC/TERT1 cells in Matrigel with cyst fluid added for 14 days). Kidney cyst fluid induced proliferation and cyst growth of renal epithelial cells in a dose-dependent fashion. Liver cyst fluid also induced cystogenesis. Using size exclusion chromatography, 56 cyst fluid fractions were obtained of which only the fractions between 30 and 100 kDa showed cystogenic potential. Mass spectrometry analysis of samples that tested positive or negative in the assay identified 43 candidate cystogenic proteins. Gene ontology analysis showed an enrichment for proteins classified as enzymes, immunity proteins, receptors, and signaling proteins. A number of these proteins have previously been implicated in ADPKD, including secreted frizzled-related protein 4, S100A8, osteopontin, and cysteine rich with EGF-like domains 1. In conclusion, both kidney and liver cyst fluids contain paracrine signaling molecules that drive cyst formation. Using size exclusion chromatography and mass spectrometry, we procured a candidate list for future studies. Ultimately, cystogenic paracrine signaling molecules may be targeted to abrogate cystogenesis in ADPKD.


Assuntos
Proliferação de Células , Líquido Cístico/metabolismo , Cistos/metabolismo , Células Epiteliais/metabolismo , Túbulos Renais Proximais/metabolismo , Hepatopatias/metabolismo , Comunicação Parácrina , Rim Policístico Autossômico Dominante/metabolismo , Transdução de Sinais , Adulto , Idoso , Linhagem Celular , Cromatografia em Gel , Cistos/patologia , Células Epiteliais/patologia , Feminino , Humanos , Túbulos Renais Proximais/patologia , Hepatopatias/patologia , Masculino , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/patologia , Proteômica/métodos , Espectrometria de Massas em Tandem
7.
Biochem Pharmacol ; 154: 175-182, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29746821

RESUMO

Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) is mediated by abnormal cyst-ling cell proliferation and fluid accumulation. Liver X receptor (LXR)-activating ligands suppresses renal cyst enlargement by modulation of cysticfibrosis transmembrane conductance regulator (CFTR)-mediated fluid accumulation. Lansoprazole has been reported as agonist of LXR, and shows an anti-proliferative effect in cancer cells. Here, lansoprazole's pharmacological effect and underlying mechanism on renal cyst development and expansion in in vitro; human ADPKD cyst-lining epithelial cell line and Type I Mardin Darby Canine Kidney (MDCK) cells, and in vivo models was investigated. Lansoprazole inhibited cyst development via inhibition of cell proliferation. In renal cells, lansoprazole's anti-proliferative effect was mediated by inhibition of mTOR/S6K and extracellular signal-regulated kinase (ERK) signaling proteins. In addition, lansoprazole inhibited CFTR-mediated fluid secretion via reduction of CFTR protein expression. In PCK rats, administering lansoprazole (50 mg/kgBW) for 4 weeks produced significant decreases in the cystic area and improved renal function by reduction of plasma creatinine and blood urea nitrogen. Inhibition of mTOR/S6K, ERK, and CFTR protein expression was observed in PCK rat kidney following lansoprazole treatment. The findings point to potential therapeutic application of lansoprazole in ADPKD.


Assuntos
Proliferação de Células/efeitos dos fármacos , Líquido Cístico/efeitos dos fármacos , Líquido Cístico/metabolismo , Lansoprazol/uso terapêutico , Doenças Renais Policísticas/tratamento farmacológico , Doenças Renais Policísticas/metabolismo , Animais , Proliferação de Células/fisiologia , Cães , Relação Dose-Resposta a Droga , Humanos , Lansoprazol/farmacologia , Células Madin Darby de Rim Canino , Masculino , Doenças Renais Policísticas/patologia , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Ratos , Ratos Transgênicos
8.
Gastrointest Endosc ; 88(1): 79-86, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29510146

RESUMO

BACKGROUND AND AIMS: The tissue acquisition and diagnostic yield of cyst fluid cytology is low-to-moderate and rarely provides a specific diagnosis. The aim of this study was to compare the tissue acquisition and diagnostic tissue yield of microforceps biopsy (MFB) with cyst fluid cytology. METHODS: In this multicenter study, data of 42 patients who had cysts both aspirated by EUS-guided FNA (EUS-FNA) and biopsy specimens were then obtained with an MFB device, were collected. Cytology analysis of cyst fluid and histologic analysis of biopsy specimens were done. Acquisition yield was defined as percentage of patients with tissue present in the aspirate or biopsy. Diagnostic tissue yield was evaluated at 3 levels: the ability of differentiation between mucinous and/or nonmucinous cysts, detection of high risk for malignancy, and specific cyst type diagnosis. RESULTS: The mean patient age was 69 years. Sixteen pancreatic cysts (38.1%) were located in the head, 17 (40.5%) in the body, and 9 (21.4%) in the tail. The mean cyst size was 28.2 mm (12-60 mm); 25 of 42 (60%) were septated. The EUS-FNA tissue (fluid) acquisition yield was 88.1% (37/42). The MFB tissue acquisition yield was 90.4% (38/42). The diagnostic cytology yield to differentiate between mucinous and/or nonmucinous cysts was 47.6% (20/42), and the MFB histologic yield to differentiate between mucinous and/or nonmucinous cysts was 61.9% (26/42) (P = .188). The percentage of cysts at high risk for malignancy by cytology was 54.7% (23/42), and MFB was 71.5% (30/42) (P = .113). However, the ability of MFB to provide a specific cyst type diagnosis was 35.7% (15/42), and that for cytology was 4.8% (2/42) (P = .001). Surgical histology was concordant with that of MFB in 6 of 7 patients (85%), and with that of cytology in 1 of 7 patients (15%). CONCLUSION: The cyst tissue acquisition yield for MFBs was 90%. Although cytology of cyst fluid and MFB were comparable in distinguishing mucinous and nonmucinous cysts and detecting cysts at high risk for malignancy, MFB was far superior to cytology for providing a specific cyst diagnosis.


Assuntos
Biópsia/instrumentação , Carcinoma Ductal Pancreático/patologia , Líquido Cístico/citologia , Neoplasias Císticas, Mucinosas e Serosas/patologia , Tumores Neuroendócrinos/patologia , Cisto Pancreático/patologia , Neoplasias Pancreáticas/patologia , Instrumentos Cirúrgicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia/métodos , Antígeno Carcinoembrionário/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/metabolismo , Líquido Cístico/metabolismo , Cistadenoma/diagnóstico , Cistadenoma/metabolismo , Cistadenoma/patologia , Cistadenoma Seroso/diagnóstico , Cistadenoma Seroso/metabolismo , Cistadenoma Seroso/patologia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/diagnóstico , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/metabolismo , Cisto Pancreático/diagnóstico , Cisto Pancreático/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo
9.
Surgery ; 163(3): 600-605, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29241991

RESUMO

BACKGROUND: The most widely accepted biochemical test for preoperative differentiation of mucinous from benign, nonmucinous pancreatic cysts is cyst fluid carcinoembryonic antigen. However, the diagnostic accuracy of carcinoembryonic antigen ranges from 70% to 86%. Based on previous work, we hypothesize that pancreatic cyst fluid glucose may be an attractive alternative to carcinoembryonic antigen. METHODS: Pancreatic cyst fluid was collected during endoscopic or operative intervention. Diagnoses were pathologically confirmed. Glucose and carcinoembryonic antigen were measured using a patient glucometer and automated analyzer/enzyme-linked immunosorbent assay. Sensitivity, specificity, accuracy, and receiver operator characteristic analyses were performed. RESULTS: Cyst fluid samples from 153 patients were evaluated (mucinous: 25 mucinous cystic neoplasms, 77 intraductal papillary mucinous neoplasms, 4 ductal adenocarcinomas; nonmucinous: 21 serous cystic neoplasms, 9 cystic neuroendocrine tumors, 14 pseudocysts, 3 solid pseudopapillary neoplasms). Median cyst fluid glucose was lower in mucinous versus nonmucinous cysts (19 vs 96 mg/dL; P < .0001). With a threshold of ≤ 50 mg/dL, cyst fluid glucose was 92% sensitive, 87% specific, and 90% accurate in diagnosing mucinous pancreatic cysts. In comparison, cyst fluid carcinoembryonic antigen with a threshold of >192 ng/mL was 58% sensitive, 96% specific, and 69% accurate. Area under the curve for glucose and CEA were similar at 0.91 and 0.92. CONCLUSION: Cyst fluid glucose has significant advantages over carcinoembryonic antigen and should be considered for use as a routine diagnostic test for pancreatic mucinous cysts.


Assuntos
Adenocarcinoma/diagnóstico , Antígeno Carcinoembrionário/metabolismo , Líquido Cístico/metabolismo , Glucose/metabolismo , Cisto Pancreático/metabolismo , Neoplasias Pancreáticas/diagnóstico , Adenocarcinoma/metabolismo , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cisto Pancreático/patologia , Cisto Pancreático/cirurgia , Neoplasias Pancreáticas/metabolismo , Sensibilidade e Especificidade
10.
Eur J Pain ; 22(3): 501-510, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29034546

RESUMO

BACKGROUND: Endometriosis is a gynaecological disease exhibiting severe pelvic pain, but the mechanism of pain production remains unknown. Bradykinin (BK) is known as an inflammatory mediator, and shows elevated levels in inflammatory diseases such as rheumatoid arthritis. In the present study, we evaluated whether BK is involved in endometriosis-related pain. METHODS: Endometriotic lesions were used for immunohistochemistry. Primary cultures of endometriotic stromal cells (ESC) were stimulated with IL-1ß and/or BK. Quantitative RT-PCR was used to evaluate the mRNA expressions of BK receptors (BKR) and endothelin-1 in ESC. The concentration of endothelin-1 in cystic fluid of endometrioma or non-endometrioma was measured with ELISA. The conditioned medium of ESC stimulated with IL-1ß and/or BK was injected intraplantarly in mice, and evaluated whether pain-related licking behaviour was elicited. RESULTS: The expressions of BK and BKR in endometriotic lesions were observed by immunohistochemistry. In vitro experiments showed that IL-1ß induced BKR-B1 and B2 on ESC. Activation of these receptors by BK significantly induced endothelin-1 expression in ESC, which was negated completely by HOE-140, a BKR-B2 antagonist. The cystic fluid of endometrioma contained higher amount of endothelin-1 compared to non-endometrioma. Intraplantar injection of the conditioned medium of ESC treated with IL-1ß and BK significantly induced licking behaviour, which was suppressed with BQ-123, an endothelin type-A receptor antagonist. CONCLUSIONS: The present study demonstrated the presence and the function of the BK axis in endometriosis, and established a potential new therapy target for endometriosis-related pain. SIGNIFICANCE: The present study demonstrated (1) the presence and the function of the BK system in endometriosis, (2) activation of BKR induced endothelin-1 in endometriotic lesion and (3) blocking endothelin-1 was effective to decrease pain.


Assuntos
Bradicinina/metabolismo , Endometriose/metabolismo , Endotelina-1/metabolismo , Dor/metabolismo , Receptores da Bradicinina/metabolismo , Células Estromais/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Antagonistas de Receptor B2 da Bradicinina/farmacologia , Estudos de Casos e Controles , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Líquido Cístico/metabolismo , Endotelina-1/efeitos dos fármacos , Endotelina-1/genética , Endotelina-1/farmacologia , Feminino , Humanos , Interleucina-1beta/farmacologia , Camundongos , Doenças Ovarianas/metabolismo , Doenças Peritoneais/metabolismo , RNA Mensageiro/metabolismo , Receptores da Bradicinina/efeitos dos fármacos , Receptores da Bradicinina/genética , Células Estromais/efeitos dos fármacos
11.
Ann Surg ; 268(2): 340-347, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28700444

RESUMO

OBJECTIVE: Preliminary work by our group suggested that proteins within the pancreatic cyst fluid (CF) may discriminate degree of IPMN dysplasia. We sought to externally validate these markers and determine whether their inclusion in a preoperative clinical nomogram could increase diagnostic accuracy. SUMMARY BACKGROUND DATA: IPMN is the most common radiographically identifiable precursor to pancreatic cancer; however, the timing and frequency of its malignant progression are unknown, and there are currently no reliable preoperative tests that can determine the grade of dysplasia in IPMN. METHODS: Clinical and radiographic data, as well as CF samples, were obtained from 149 patients who underwent resection for IPMN at 1 of 3 institutions. High-risk disease was defined as the presence of high-grade dysplasia or invasive carcinoma. Multianalyte bead array analysis (Luminex) of CF was performed for 4 protein markers that were previously associated with high-risk disease. Logistic regression models were fit on training data, with and without adjustment for a previously developed clinical nomogram and validated with an external testing set. The models incorporating clinical risk score were presented graphically as nomograms. RESULTS: Within the group of 149 resected patients, 89 (60%) had low-risk disease, and 60 (40%) had high-risk disease. All 4 CF markers (MMP9, CA72-4, sFASL, and IL-4) were overexpressed in patients with high-risk IPMN (P < 0.05). Two predictive models based on preselected combinations of CF markers had concordance indices of 0.76 (Model-1) and 0.80 (Model-2). Integration of each CF marker model into a previously described clinical nomogram leads to increased discrimination compared with either the CF models or nomogram alone (c-indices of 0.84 and 0.83, respectively). CONCLUSIONS: This multi-institutional study validated 2 CF protein marker models for preoperative identification of high-risk IPMN. When combined with a clinical nomogram, the ability to predict high-grade dysplasia was even stronger.


Assuntos
Biomarcadores Tumorais/metabolismo , Líquido Cístico/metabolismo , Técnicas de Apoio para a Decisão , Neoplasias Intraductais Pancreáticas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/cirurgia , Bases de Dados Factuais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Nomogramas , Neoplasias Intraductais Pancreáticas/metabolismo , Neoplasias Intraductais Pancreáticas/cirurgia , Cuidados Pré-Operatórios/métodos , Radiografia , Medição de Risco
12.
J Neuropathol Exp Neurol ; 76(9): 779-788, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28859336

RESUMO

Pediatric adamantinomatous craniopharyngioma (ACP) is a highly solid and cystic tumor, often causing substantial damage to critical neuroendocrine structures such as the hypothalamus, pituitary gland, and optic apparatus. Paracrine signaling mechanisms driving tumor behavior have been hypothesized, with IL-6R overexpression identified as a potential therapeutic target. To identify potential novel therapies, we characterized inflammatory and immunomodulatory factors in ACP cyst fluid and solid tumor components. Cytometric bead analysis revealed a highly pro-inflammatory cytokine pattern in fluid from ACP compared to fluids from another cystic pediatric brain tumor, pilocytic astrocytoma. Cytokines and chemokines with particularly elevated concentrations in ACPs were IL-6, CXCL1 (GRO), CXCL8 (IL-8) and the immunosuppressive cytokine IL-10. These data were concordant with solid tumor compartment transcriptomic data from a larger cohort of ACPs, other pediatric brain tumors and normal brain. The majority of receptors for these cytokines and chemokines were also over-expressed in ACPs. In addition to IL-10, the established immunosuppressive factor IDO-1 was overexpressed by ACPs at the mRNA and protein levels. These data indicate that ACP cyst fluids and solid tumor components are characterized by an inflammatory cytokine and chemokine expression pattern. Further study regarding selective cytokine blockade may inform novel therapeutic interventions.


Assuntos
Craniofaringioma/metabolismo , Líquido Cístico/metabolismo , Citocinas/metabolismo , Neoplasias Hipofisárias/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Craniofaringioma/genética , Craniofaringioma/patologia , Líquido Cístico/imunologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Análise em Microsséries , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , RNA Mensageiro/metabolismo , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/metabolismo
13.
J Am Coll Surg ; 225(4): 481-487, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28739154

RESUMO

BACKGROUND: With the increased frequency of diagnostic imaging, pancreatic cysts are now detected in >3% of American adults. Most of these are intraductal papillary mucinous neoplasms (IPMNs) with well-established but variable malignant potential. A biomarker that predicts malignant potential or dysplastic grade would help determine which IPMNs require removal and which can be observed safely. We previously reported that pancreatic fluid prostaglandin E2 (PGE2) levels might have promise as a predictor of IPMN dysplasia and we seek to validate those results in the current study. STUDY DESIGN: Pancreatic cyst/duct fluid was prospectively collected from 100 patients with IPMN undergoing pancreatic resection. Surgical pathology revealed 47 low-/moderate-grade, 34 high-grade, and 20 invasive IPMNs. The PGE2 levels were assessed by ELISA and correlated with IPMN dysplasia grade, demographics, clinical radiologic/pathologic variables, acute/chronic pancreatitis, and NSAID use. RESULTS: Mean pancreatic cyst fluid PGE2 levels in high-grade and invasive IPMNs were significantly higher than low-/moderate-grade IPMNs (3.5 and 4.4 pg/µL, respectively, vs 1.2 pg/µL; p < 0.0016). At a threshold of 1.1 pg/µL, PGE2 was 63% sensitive, 79% specific, and 71% accurate for detection of high-grade/invasive IPMNs. When tested in the subset of IPMN patients with preoperative pancreatic cyst fluid CEA >192 ng/mL, PGE2 at a threshold of 0.5 pg/µL demonstrated 78% sensitivity, 100% specificity, and 86% accuracy for detection of high-grade/invasive IPMN. CONCLUSIONS: Our results validate pancreatic cyst fluid PGE2 as an indicator of IPMN dysplasia, especially in select patients with preoperative pancreatic cyst fluid CEA >192 ng/mL. The inclusion of PGE2/CEA in a diagnostic biomarker panel can facilitate more optimal treatment stratification of IPMN patients.


Assuntos
Adenocarcinoma Mucinoso/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Dinoprostona/metabolismo , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Biomarcadores/metabolismo , Carcinoma Ductal Pancreático/patologia , Estudos de Coortes , Líquido Cístico/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia
14.
J Gastrointest Surg ; 21(10): 1599-1605, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28516310

RESUMO

OBJECTIVE: The aim of this study was to evaluate the outcome of patients presumed to have mucinous cysts of the pancreas who were initially selected for radiographic surveillance. METHODS: Patients with a pancreatic cyst and a measured cyst fluid carcinoembryonic antigen (CEA) ≥192 ng/mL were included. Patients were stratified by those who underwent initial resection and those who were recommended for radiographic surveillance. The natural history of these two groups was examined. RESULTS: From 1999 to 2014, 227 patients were identified who had a cyst fluid CEA ≥192 ng/mL (median 961, range 192-300,000 ng/mL). Immediate resection was performed on 63 patients (28%). Initial radiographic surveillance was recommended for 164 patients; 87% did not have main pancreatic duct dilation, and 87% met consensus criteria for radiographic surveillance. After a median follow-up of 56 months, 48 of the 164 patients (29%) had undergone resection. Ultimately, there were three cases (2%) of high-grade dysplasia and two cases of invasive carcinoma (1%) within these 164 patients selected for observation. Three of the five cases of either high-grade dysplasia or invasive carcinoma were among the 22 patients followed outside of consensus guidelines. CONCLUSIONS: Appropriately selected patients with mucinous pancreatic cysts can be safely followed with serial surveillance with a low risk of malignant progression.


Assuntos
Carcinoma/diagnóstico por imagem , Cisto Pancreático/diagnóstico por imagem , Cisto Pancreático/cirurgia , Neoplasias Pancreáticas/diagnóstico por imagem , Conduta Expectante , Adulto , Assistência ao Convalescente , Idoso , Idoso de 80 Anos ou mais , Antígeno Carcinoembrionário/metabolismo , Líquido Cístico/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Pancreatectomia , Radiografia , Estudos Retrospectivos
15.
Endoscopy ; 49(9): 866-873, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28511236

RESUMO

Background and study aims The aim of this study was to investigate the long-term outcomes after endoscopic ultrasound (EUS)-guided pancreatic cyst ablation. Patients and methods In a single-center, prospective study, 164 patients with pancreatic cysts underwent EUS-guided cyst ablation using ethanol with paclitaxel. The inclusion criteria were as follows: unilocular or oligolocular cysts; clinically indeterminate cysts that required EUS fine-needle aspiration; and/or cysts that grew during the observation period. Treatment response was classified as complete resolution, partial resolution, or persistent cyst, with < 5 %, 5 % - 25 %, and 25 % of the original cyst volume, respectively. Results The median largest diameter of the cyst was 32 mm and the median volume was 17.1 mL. Based on cyst fluid analysis there were 71 mucinous cystic neoplasms, 16 serous cystic neoplasms, 11 intraductal papillary mucinous neoplasms, 3 pseudocysts, and 63 indeterminate cysts. Sixteen treated patients (9.8 %) had adverse events (1 severe, 4 moderate, and 11 mild). Treatment response was as follows: complete resolution in 114 (72.2 %), partial resolution in 31 (19.6 %), and persistent cysts in 13 (8.2 %). Twelve of the 13 patients with persistent cysts underwent surgery. During clinical and imaging follow-up (median 72 months, interquartile range 50 - 85 months) of the 114 patients with complete resolution, only two patients (1.7 %) showed cyst recurrence. Based on multivariate analysis, the absence of septa (odds ratio [OR] 7.12, 95 % confidence interval [CI] 2.72 - 18.67) and cyst size less than 35 mm (OR 2.39, 95 %CI 1.11 - 5.16) predicted complete resolution. Conclusion Among patients with pancreatic cysts in whom complete resolution was achieved after EUS-guided cyst ablation, 98.3 % remained in remission at 6-year follow-up. Unilocular form and small cyst size were predictive of complete resolution. This treatment approach may be an effective and durable alternative to surgery.Trial registered at ClinicalTrials.gov (NCT 00689715).


Assuntos
Técnicas de Ablação , Neoplasias Císticas, Mucinosas e Serosas/cirurgia , Cisto Pancreático/cirurgia , Neoplasias Pancreáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/administração & dosagem , Antígeno Carcinoembrionário/metabolismo , Líquido Cístico/citologia , Líquido Cístico/metabolismo , Endossonografia , Etanol/administração & dosagem , Feminino , Humanos , Injeções Intralesionais , Masculino , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/diagnóstico , Neoplasias Císticas, Mucinosas e Serosas/patologia , Paclitaxel/administração & dosagem , Cisto Pancreático/diagnóstico , Cisto Pancreático/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Solventes/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia de Intervenção , Adulto Jovem
16.
Brain Pathol ; 27(3): 370-376, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28414889

RESUMO

Adamantinomatous craniopharyngioma (ACP) is still often burdened by a poor prognosis in children as far as the risk of recurrence and the quality of life are concerned. Therefore, many efforts are now dedicated to investigate the molecular characteristics of this tumor aiming at finding new therapeutic options. ACP is prevalently a cystic lesion so that an increasing number of researches are focused on the analysis of its cystic content. In the present article, the main results of the current proteomic analysis (PA) on the ACP fluid are summarized. Both "bottom-up" and "top-down" approaches have been utilized. In the bottom-up approach, proteins and peptides are enzymatically or chemically digested prior to liquid chromatography and mass spectrometry analyses. The bottom-up approach pointed out several proteins of the inflammation (namely, α2-HS-glycoprotein, α1-antichymotrypsin and apolipoproteins) as possibly involved in the genesis and growth of the cystic component of ACP. The top-down strategy analyzes proteins and peptides in the intact state, making it particularly suitable for the identification of peptides and low molecular weight proteins and for the characterization of their possible isoforms and post-translational modifications. The top-down approach disclosed the presence of the thymosin ß family. Thymosin ß4, in particular, which is involved in the cytoskeleton organization and migration of several tumors, could play a role in the progression of ACP. Finally, PA was utilized to investigate alterations in cyst fluid character after treatment with interferon-α. The analyzed samples showed a progressive reduction of the levels of α-defensins (proteins involved in the inflammatory-mediated response) after the intracystic injection of interferon-α, thus reinforcing the hypothesis that inflammation contributes to ACP cyst pathogenesis. Additional studies on the solid component of ACP are still necessary to further validate the previous results and to identify possible markers for targeted therapy.


Assuntos
Craniofaringioma/metabolismo , Neoplasias Hipofisárias/metabolismo , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Líquido Cístico/metabolismo , Feminino , Humanos , Masculino , Espectrometria de Massas , Projetos Piloto , Proteômica/métodos
18.
Clin Cancer Res ; 23(14): 3935-3944, 2017 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-28148542

RESUMO

Purpose: Pancreatic cysts are common and pose diagnostic and management challenges. Pancreatic cyst fluid markers have the potential to aid in the management of cysts with concerning imaging findings. Our aim was to evaluate cyst fluid methylated DNA markers for their accuracy for predicting the histologic grade of neoplastic pancreatic cysts.Experimental Design: Pancreatic cyst fluid samples from 183 patients (29 discovery and 154 validation) aspirated after surgical resection were analyzed for methylated DNA at selected genes (SOX17, BNIP3, FOXE1, PTCHD2, SLIT2, EYA4, and SFRP1) using methylation-specific droplet-digital PCR (dd-QMSP). Methylated DNA levels were evaluated for their accuracy at predicting the grade of dysplasia of the pancreatic cyst.Results: All six markers evaluated in the validation set could accurately distinguish high-risk cystic neoplasms (with high-grade dysplasia and/or associated invasive cancer) from low-risk cysts (lower grades of dysplasia) with accuracies from 79.8% to 83.6%. Methylated SOX17 had the highest overall accuracy as a single marker (sensitivity, 78.4%; specificity, 85.6%; accuracy 83.6%, cutoff; 25 methylated DNA molecules/µL cyst fluid). The best four-gene combination had 84.3% sensitivity, 89.4% specificity, and 88.0% accuracy at distinguishing cysts with high-grade dysplasia and/or invasive cancer from those without. All six markers were independent predictors of having invasive cancer/high-grade dysplasia after adjusting for clinical/imaging factors known to be associated with grade of dysplasia. The combination of methylated SOX17 with cytology better predicted neoplastic grade than cytology alone.Conclusions: A panel of methylated gene markers quantified by dd-QMSP can be used to predict the grade of dysplasia of pancreatic cysts. Clin Cancer Res; 23(14); 3935-44. ©2017 AACR.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/diagnóstico , Fatores de Transcrição SOXF/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Líquido Cístico/citologia , Líquido Cístico/metabolismo , Citodiagnóstico , Metilação de DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Proteínas de Neoplasias/classificação , Cisto Pancreático/genética , Cisto Pancreático/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
19.
Medicine (Baltimore) ; 96(1): e5513, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28072692

RESUMO

BACKGROUND: Management of pancreatic cysts is based on neoplastic-nonneoplastic discrimination. Endoscopic ultrasound (EUS) enables to differentiate neoplastic-nonneoplastic lesions and also allows fine-needle aspiration (FNA). In this study, we aim to assess feasibility and clinical relevance of cytological and biochemical analysis in differential diagnosis of cystic pancreatic lesions in patients who had undergone endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) due to pancreatic cysts. METHODS: Participants were 96 patients who had undergone EUS-FNA for differential diagnosis of pancreatic cysts. Pancreatic cysts were classified as benign-mucinous, nonmucinous, and malignant according to patient history, physical examination, EUS appearance, and cystic fluid assessment. Tumor markers (CEA, CA(cancer antigens) 72.4, CA 19-9) , amylase, lipase and cytological assesment were compared between 3 different groups. Receiver-operating characteristics (ROC) curves were constructed to identify appropriate cut-off values. RESULTS: Fluid CEA and CA 72.4 levels for benign-mucinous and malignant cysts were significantly higher than for nonmucinous cysts (P ≤ 0.04). A cut-off CEA level of 207 ng/mL differentiated mucinous etiology with a sensitivity of 72.7%, specificity of 97.7%, and accuracy of 89.5%. The sensitivity, specificity, and accuracy of the CA 72.4 cut-off level of 3.32 ng/mL were 80%, 69.5%, and 73.6%, respectively. CONCLUSION: Cyst fluid CEA and CA 72.4 levels have a high accuracy in discriminating mucinous from nonmucinous cysts. When combined with cytology their accuracy rate increases.


Assuntos
Antígenos Glicosídicos Associados a Tumores/análise , Antígeno Carcinoembrionário/análise , Líquido Cístico , Cisto Pancreático , Neoplasias Pancreáticas , Adulto , Idoso , Biomarcadores Tumorais/análise , Estudos de Coortes , Líquido Cístico/química , Líquido Cístico/metabolismo , Diagnóstico Diferencial , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cisto Pancreático/química , Cisto Pancreático/diagnóstico , Cisto Pancreático/metabolismo , Cisto Pancreático/patologia , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Turquia
20.
Magn Reson Med Sci ; 16(2): 137-145, 2017 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-27646154

RESUMO

PURPOSE: Heme and iron accumulation due to repeated hemorrhage in endometriosis may contribute to a pivotal role in carcinogenesis. We evaluate the clinical application of MR relaxometry in a series of ovarian endometriosis (OE) and endometriosis-associated ovarian cancer (EAOC). MATERIALS AND METHODS: A prospective study of diagnostic accuracy was conducted among 82 patients (67 OE and 15 EAOC) to compare MR relaxometry and biochemical measurement of cyst fluid total iron concentration. Transverse relaxation rate R2 value was determined using a single-voxel, multi-echo MR sequence (HISTO) by a 3T-MR system. Phantom experiments were also performed to assess the correlation between the ex vivo R2 values and total iron concentrations. RESULTS: Both the results of phantom experiments and in vivo human data confirmed that in vivo R2 values were highly correlated with total iron concentrations. Compared to OE, EAOC exhibit decreased in vivo R2 values and total iron levels, regardless of their age, menopausal status and cyst size. The use of in vivo R2 values retained excellent accuracy in distinguishing EAOC versus OE (sensitivity and specificity: 86% and 94%). CONCLUSIONS: We have demonstrated that MR relaxometry provides a noninvasive predictive tool to discriminate between EAOC and OE.


Assuntos
Transformação Celular Neoplásica/patologia , Líquido Cístico/metabolismo , Endometriose/patologia , Imagem por Ressonância Magnética , Neoplasias Ovarianas/patologia , Adulto , Idoso , Transformação Celular Neoplásica/metabolismo , Estudos de Coortes , Endometriose/diagnóstico por imagem , Endometriose/metabolismo , Feminino , Humanos , Ferro/metabolismo , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/metabolismo , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
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