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1.
J Hepatol ; 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34627976

RESUMO

BACKGROUND & AIMS: Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of NAFLD. However, the underlying mechanisms linking EC exposure with NAFLD remain poorly understood and there is no data on their impact on the human liver metabolome. Herein, we hypothesized that exposure to ECs, particularly perfluorinated alkyl substances (PFAS), impacts liver metabolism, specifically bile acid metabolism. METHODS: In a well-characterized human NAFLD cohort of 105 individuals, we investigated the effects of EC exposure on liver metabolism. We characterized the liver (via biopsy) and circulating metabolomes using four mass spectrometry-based analytical platforms, and measured PFAS and other ECs in serum. We subsequently compared these results with an exposure study in a PPARα-humanized mouse model. RESULTS: PFAS exposure appears associated with perturbation of key hepatic metabolic pathways previously found altered in NAFLD, particularly as regards bile acid and lipid metabolism. We identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables (liver fat content, HOMA-IR), in female subjects versus males. Specifically, we observed PFAS-associated up-regulation of bile acids, triacylglycerols and ceramides, and association between chemical exposure and dysregulated glucose metabolism in females. The murine exposure study further corroborated our findings, vis-à-vis a sex-specific association between PFAS exposure and NAFLD-associated lipid changes. CONCLUSIONS: Females may be more sensitive to the harmful impacts of PFAS. Lipid-related changes subsequent to PFAS exposure may be secondary to the interplay between PFAS and bile acid metabolism. LAY SUMMARY: There is increasing evidence that specific environmental contaminants such, as per- and polyfluoroalkyl substances (PFAS), contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, it is poorly understood how these chemicals impact human liver metabolism. Here we show that human exposure to PFAS impacts liver metabolic processes associated with NAFLD, and does so in a sexually-dimorphic manner.

2.
Eur J Endocrinol ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34606470

RESUMO

OBJECTIVE: Parathyroid carcinoma (PC), atypical parathyroid tumors (APT) and parathyroid adenoma (PA) present with hypercalcemia. Diminished calcium-sensing receptor (CaSR) expression is reported in PC but is rare in benign tumours. Filamin A (FLNA) binds to the CaSR and activates the mitogen-activated protein kinase (MAPK) signalling pathway. FLNA is related to tumour aggressiveness in several cancers, but its role in parathyroid neoplasia is unknown. DESIGN: We examined FLNA, CaSR and parafibromin expression in PCs (n = 32), APTs (n = 44) and PAs (n = 77) and investigated their potential as diagnostic and/or prognostic markers. METHODS: Tissue microarray slides were immunohistochemically stained with FLNA, CaSR and parafibromin. Staining results were correlated with detailed clinical data. RESULTS: All tumours stained positively for CaSR, with two tumours (one PC and one APT) showing diminished expression. Carcinomas were characterized by increased cytoplasmic FLNA expression compared to APTs and PAs (p = 0.004). FLNA expression was not correlated with Ki-67 proliferation index or loss of parafibromin expression. Cytoplasmic FLNA expression was also associated with higher serum calcium, PTH concentrations and male sex (p = 0.014, p = 0.017 and p = 0.049, respectively). Using a combined marker score, we found that parathyroid tumours with low FLNA expression and positive parafibromin staining were extremely likely to be benign (p < 0.001). CONCLUSION: Cytoplasmic and membranous FLNA expression is increased in parathyroid carcinomas compared to benign tumours. A combined FLNA and parafibromin expression score shows potential as a prognostic predictor of indolent behaviour in parathyroid neoplasms.

3.
Endocr Connect ; 10(9): 1055-1064, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34348234

RESUMO

Mixed neuroendocrine-non-neuroendocrine neoplasms (MINEN) are rare tumors that consist of at least 30% of both neuroendocrine and non-neuroendocrine components. The data concerning the pathogenesis of MINEN suggest a monoclonal origin. We describe a spontaneously immortalized cell line derived from gastric MINEN called GNEN-1. Primary tumor consisted of components of high-grade neuroendocrine carcinoma and adenocarcinoma. The GNEN-1 cell line was initiated from metastatic tumor cells of peritoneal fluid and expresses a purely neuroendocrine phenotype. The GNEN-1 cell line grows as monolayers and has retained the neuroendocrine phenotype with positivity for chromogranin A in immunohistochemistry. Electron microscopy showed cytoplasmic dense core granules and axon hillocks. The karyotype revealed alterations typical of both adenocarcinoma and neuroendocrine carcinoma such as trisomy 7 and 8. GNEN-1 cells were also positive for stanniocalcin-1, a marker of poor prognosis in gastric carcinomas. Expression of several markers related to neuroendocrine tumors was found. There have been only a few studies on the pathogenesis of MINEN and management of the disease due to the rarity of this tumor type. Here we describe for the first time an immortalized cell line derived from mixed gastric NEN. The GNEN-1 line offers a tool for future research on gastric NEN.

4.
Eur J Endocrinol ; 185(4): 577-586, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34374651

RESUMO

Objective: Insulinomas are rare functional pancreatic neuroendocrine tumours. As previous data on the long-term prognosis of insulinoma patients are scarce, we studied the morbidity and mortality in the Finnish insulinoma cohort. Design: Retrospective cohort study. Methods: Incidence of endocrine, cardiovascular, gastrointestinal and psychiatric disorders, and cancers was compared in all the patients diagnosed with an insulinoma in Finland during 1980-2010 (n = 79, including two patients with multiple endocrine neoplasia type 1 syndrome), vs 316 matched controls, using the Mantel-Haenszel method. Overall survival was analysed with Kaplan-Meier and Cox regression analyses. Results: The median length of follow-up was 10.7 years for the patients and 12.2 years for the controls. The long-term incidence of atrial fibrillation (rate ratio (RR): 2.07 (95% CI: 1.02-4.22)), intestinal obstruction (18.65 (2.09-166.86)), and possibly breast (4.46 (1.29-15.39) and kidney cancers (RR not applicable) was increased among insulinoma patients vs controls, P < 0.05 for all comparisons. Endocrine disorders and pancreatic diseases were more frequent in the patients during the first year after insulinoma diagnosis, but not later on. The survival of patients with a non-metastatic insulinoma (n = 70) was similar to that of controls, but for patients with distant metastases (n = 9), the survival was significantly impaired (median 3.4 years). Conclusions: The long-term prognosis of patients with a non-metastatic insulinoma is similar to the general population, except for an increased incidence of atrial fibrillation, intestinal obstruction, and possibly breast and kidney cancers. These results need to be confirmed in future studies. Metastatic insulinomas entail a markedly decreased survival.


Assuntos
Insulinoma/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Comorbidade , Finlândia/epidemiologia , Seguimentos , História do Século XX , História do Século XXI , Humanos , Incidência , Insulinoma/complicações , Insulinoma/diagnóstico , Insulinoma/mortalidade , Pessoa de Meia-Idade , Morbidade , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo
5.
Hum Mol Genet ; 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34274970

RESUMO

Many hereditary cancer syndromes are associated with an increased risk of small and large intestinal adenocarcinomas. However, conditions bearing a high risk to both adenocarcinomas and neuroendocrine tumors are yet to be described. We studied a family with 16 individuals in four generations affected by a wide spectrum of intestinal tumors, including hyperplastic polyps, adenomas, small intestinal neuroendocrine tumors, and colorectal and small intestinal adenocarcinomas. To assess the genetic susceptibility and understand the novel phenotype we utilized multiple molecular methods, including whole genome sequencing, RNA sequencing, single cell sequencing, RNA in situ hybridization, and organoid culture. We detected a heterozygous deletion at the cystic fibrosis locus (7q31.2) perfectly segregating with the intestinal tumor predisposition in the family. The deletion removes a topologically associating domain (TAD) border between CFTR and WNT2, aberrantly activating WNT2 in the intestinal epithelium. These consequences suggest that the deletion predisposes to small intestinal neuroendocrine tumors and small and large intestinal adenocarcinomas, and reveals the broad tumorigenic effects of aberrant WNT activation in the human intestine.

6.
Acta Oncol ; 60(7): 931-941, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33999752

RESUMO

BACKGROUND: The diagnostic work-up and treatment of patients with gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) has undergone major advances and new methods are introduced. Furthermore, an update of the WHO classification has resulted in a new nomenclature for GEP-NEN that is implemented in the clinic. AIM: These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat GEP-NEN patients and aims to be useful in the daily practice for clinicians.


Assuntos
Neoplasias Gastrointestinais , Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/tratamento farmacológico , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/terapia
7.
Diagn Pathol ; 16(1): 41, 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33957930

RESUMO

BACKGROUND: The objective was to build a novel method for automated image analysis to locate and quantify the number of cytokeratin 7 (K7)-positive hepatocytes reflecting cholestasis by applying deep learning neural networks (AI model) in a cohort of 210 liver specimens. We aimed to study the correlation between the AI model's results and disease progression. The cohort of liver biopsies which served as a model of chronic cholestatic liver disease comprised of patients diagnosed with primary sclerosing cholangitis (PSC). METHODS: In a cohort of patients with PSC identified from the PSC registry of the University Hospital of Helsinki, their K7-stained liver biopsy specimens were scored by a pathologist (human K7 score) and then digitally analyzed for K7-positive hepatocytes (K7%area). The digital analysis was by a K7-AI model created in an Aiforia Technologies cloud platform. For validation, values were human K7 score, stage of disease (Metavir and Nakunuma fibrosis score), and plasma liver enzymes indicating clinical cholestasis, all subjected to correlation analysis. RESULTS: The K7-AI model results (K7%area) correlated with the human K7 score (0.896; p < 2.2e- 16). In addition, K7%area correlated with stage of PSC (Metavir 0.446; p < 1.849e- 10 and Nakanuma 0.424; p < 4.23e- 10) and with plasma alkaline phosphatase (P-ALP) levels (0.369, p < 5.749e- 5). CONCLUSIONS: The accuracy of the AI-based analysis was comparable to that of the human K7 score. Automated quantitative image analysis correlated with stage of PSC and with P-ALP. Based on the results of the K7-AI model, we recommend K7 staining in the assessment of cholestasis by means of automated methods that provide fast (9.75 s/specimen) quantitative analysis.

9.
Nutrients ; 13(1)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429859

RESUMO

Only some individuals with obesity develop liver fibrosis due to non-alcoholic fatty liver disease (NAFLD-fibrosis). We determined whether detailed assessment of lifestyle factors in addition to physical, biochemical and genetic factors helps in identification of these patients. A total of 100 patients with obesity (mean BMI 40.0 ± 0.6 kg/m2) referred for bariatric surgery at the Helsinki University Hospital underwent a liver biopsy to evaluate liver histology. Physical activity was determined by accelerometer recordings and by the Modifiable Activity Questionnaire, diet by the FINRISK Food Frequency Questionnaire, and other lifestyle factors, such as sleep patterns and smoking, by face-to-face interviews. Physical and biochemical parameters and genetic risk score (GRS based on variants in PNPLA3, TM6SF2, MBOAT7 and HSD17B13) were measured. Of all participants 49% had NAFLD-fibrosis. Independent predictors of NAFLD-fibrosis were low moderate-to-vigorous physical activity, high red meat intake, low carbohydrate intake, smoking, HbA1c, triglycerides and GRS. A model including these factors (areas under the receiver operating characteristics curve (AUROC) 0.90 (95% CI 0.84-0.96)) identified NAFLD-fibrosis significantly more accurately than a model including all but lifestyle factors (AUROC 0.82 (95% CI 0.73-0.91)) or models including lifestyle, physical and biochemical, or genetic factors alone. Assessment of lifestyle parameters in addition to physical, biochemical and genetic factors helps to identify obese patients with NAFLD-fibrosis.


Assuntos
Estilo de Vida , Cirrose Hepática/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade/complicações , Adulto , Cirurgia Bariátrica , Dieta , Exercício Físico , Feminino , Predisposição Genética para Doença , Humanos , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estudos Prospectivos , Sono , Fatores Socioeconômicos , Estresse Psicológico
10.
IEEE J Biomed Health Inform ; 25(2): 422-428, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32750899

RESUMO

The quantity of leukocytes in papillary thyroid carcinoma (PTC) potentially have prognostic and treatment predictive value. Here, we propose a novel method for training a convolutional neural network (CNN) algorithm for segmenting leukocytes in PTCs. Tissue samples from two retrospective PTC cohort were obtained and representative tissue slides from twelve patients were stained with hematoxylin and eosin (HE) and digitized. Then, the HE slides were destained and restained immunohistochemically (IHC) with antibodies to the pan-leukocyte anti CD45 antigen and scanned again. The two stain-pairs of all representative tissue slides were registered, and image tiles of regions of interests were exported. The image tiles were processed and the 3,3'-diaminobenzidine (DAB) stained areas representing anti CD45 expression were turned into binary masks. These binary masks were applied as annotations on the HE image tiles and used in the training of a CNN algorithm. Ten whole slide images (WSIs) were used for training using a five-fold cross-validation and the remaining two slides were used as an independent test set for the trained model. For visual evaluation, the algorithm was run on all twelve WSIs, and in total 238,144 tiles sized 500 × 500 pixels were analyzed. The trained CNN algorithm had an intersection over union of 0.82 for detection of leukocytes in the HE image tiles when comparing the prediction masks to the ground truth anti CD45 mask. We conclude that this method for generating antibody supervised annotations using the destain-restain IHC guided annotations resulted in high accuracy segmentations of leukocytes in HE tissue images.

11.
J Clin Endocrinol Metab ; 106(1): e300-e315, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33064150

RESUMO

CONTEXT: The I148M (rs738409-G) variant in PNPLA3 increases liver fat content but may be protective against cardiovascular disease. Insulin resistance (IR) amplifies the effect of PNPLA3-I148M on liver fat. OBJECTIVE: To study whether PNPLA3-I148M confers an antihyperlipidemic effect in insulin-resistant patients. DESIGN: Cross-sectional study comparing the impact of PNPLA3-I148M on plasma lipids and lipoproteins in 2 cohorts, both divided into groups based on rs738409-G allele carrier status and median HOMA-IR. SETTING: Tertiary referral center. PATIENTS: A total of 298 obese patients who underwent a liver biopsy during bariatric surgery (bariatric cohort: age 49 ±â€…9 years, body mass index [BMI] 43.2 ±â€…6.8 kg/m2), and 345 less obese volunteers in whom liver fat was measured by proton magnetic resonance spectroscopy (nonbariatric cohort: age 45 ±â€…14 years, BMI 29.7 ±â€…5.7 kg/m2). MAIN OUTCOME MEASURES: Nuclear magnetic resonance profiling of plasma lipids, lipoprotein particle subclasses and their composition. RESULTS: In both cohorts, individuals carrying the PNPLA3-I148M variant had significantly higher liver fat content than noncarriers. In insulin-resistant and homozygous carriers, PNPLA3-I148M exerted a distinct antihyperlipidemic effect with decreased very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles and their constituents, and increased high-density lipoprotein particles and their constituents, compared with noncarriers. VLDL particles were smaller and LDL particles larger in PNPLA3-I148M carriers. These changes were geometrically opposite to those due to IR. PNPLA3-I148M did not have a measurable effect in patients with lower IR, and its effect was smaller albeit still significant in the less obese than in the obese cohort. CONCLUSIONS: PNPLA3-I148M confers an antiatherogenic plasma lipid profile particularly in insulin-resistant individuals.

12.
PLoS One ; 15(12): e0243900, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33315908

RESUMO

Gastroenteropancreatic neuroendocrine neoplasms grade 3 (GEP-NENs G3) are rare tumors. These highly aggressive neoplasms are traditionally treated with platinum-based chemotherapy in combination with etoposide. Immune checkpoint proteins such as programmed cell death ligand (PD-L1) may have a role in different cancers allowing them escape the immune system and hence, progress. We aimed to investigate the immunohistochemical expression of PD-L1 in GEP-NEN G3 and evaluate its correlation to clinical parameters. In a cohort of 136 patients, 14 (10%) expressed PD-L1 immunoreactivity; four (3%) patients in the tumor cells and 10 (7%) had immunoreactive immune cells. PD-L1 expression did not correlate to clinical parameters, progression-free survival or overall survival. We conclude that PD-L1 expression is present only in a subset of GEP-NEN G3 patients. Further studies are needed to fully understand the role of PD-L1 in patients with GEP-NEN G3, including the future possibility for treatment with immune checkpoint inhibitors.


Assuntos
Antígeno B7-H1/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Intestinais/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Feminino , Humanos , Neoplasias Intestinais/imunologia , Neoplasias Intestinais/patologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia
13.
Eur J Endocrinol ; 183(6): 539-550, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33055298

RESUMO

Objective: Endocrine Society guidelines recommend adrenal venous sampling (AVS) in primary aldosteronism (PA) if adrenalectomy is considered. We tested whether functional imaging of adrenal cortex with 11C-metomidate (11C-MTO) could offer a noninvasive alternative to AVS in the subtype classification of PA. Design: We prospectively recruited 58 patients with confirmed PA who were eligible for adrenal surgery. Methods: Subjects underwent AVS and 11C-MTO-PET without dexamethasone pretreatment in random order. The lateralization of 11C-MTO-PET and adrenal CT were compared with AVS in all subjects and in a prespecified adrenalectomy subgroup in which the diagnosis was confirmed with immunohistochemical staining for CYP11B2. Results: In the whole study population, the concordance of AVS and 11C-MTO-PET was 51% and did not differ from that of AVS and adrenal CT (53%). The concordance of AVS and 11C-MTO-PET was 55% in unilateral and 44% in bilateral PA. In receiver operating characteristics analysis, the maximum standardized uptake value ratio of 1.16 in 11C-MTO-PET had an AUC of 0.507 (P = n.s.) to predict allocation to adrenalectomy or medical therapy with sensitivity of 55% and specificity of 44%. In the prespecified adrenalectomy subgroup, AVS and 11C-MTO-PET were concordant in 10 of 19 subjects with CYP11B2-positive adenoma and in 6 of 10 with CYP11B2-positivity without an adenoma. Conclusions: The concordance of 11C-MTO-PET with AVS was clinically suboptimal, and did not outperform adrenal CT. In a subgroup with CYP11B2-positive adenoma, 11C-MTO-PET identified 53% of cases. 11C-MTO-PET appeared to be inferior to AVS for subtype classification of PA.


Assuntos
Radioisótopos de Carbono/metabolismo , Hiperaldosteronismo/diagnóstico por imagem , Hiperaldosteronismo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Córtex Suprarrenal/diagnóstico por imagem , Córtex Suprarrenal/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
14.
APMIS ; 128(11): 563-572, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32794589

RESUMO

Neuroendocrine tumors (NETs) are often diagnosed from the metastases of an unknown primary tumor. Specific immunohistochemical (IHC) markers indicating the location of a primary tumor are needed. The proprotein convertase subtilisin/kexin type 2 (PCSK2) is found in normal neural and neuroendocrine cells, and known to express in NETs. We investigated the tissue microarray (TMA) of 86 primary tumors from 13 different organs and 9 metastatic NETs, including primary tumor-metastasis pairs, for PCSK2 expression with polymer-based IHC. PCSK2 was strongly positive in all small intestine and appendiceal NETs, the so-called midgut NETs, in most pheochromocytomas and paragangliomas, and in some of the typical and atypical pulmonary carcinoid tumors. NETs showing strong positivity were re-evaluated in larger tumor cohorts confirming the primary observation. In the metastases, the expression of PCSK2 mirrored that of the corresponding primary tumors. We found negative or weak staining in NETs from the thymus, gastric mucosa, pancreas, rectum, thyroid, and parathyroid. PCSK2 expression did not correlate with Ki-67 in well-differentiated NETs. Our data suggest that PCSK2 positivity can indicate the location of the primary tumor. Thus, PCSK2 could function in the IHC panel determined from screening metastatic NET biopsies of unknown primary origins.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Carcinoma Neuroendócrino/genética , Neoplasias Gastrointestinais/genética , Neoplasias Pulmonares/genética , Tumores Neuroendócrinos/genética , Paraganglioma/genética , Feocromocitoma/genética , Pró-Proteína Convertase 2/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Biomarcadores Tumorais/genética , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Cromogranina A/genética , Feminino , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/cirurgia , Expressão Gênica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Metástase Linfática , Masculino , Estadiamento de Neoplasias , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Paraganglioma/diagnóstico , Paraganglioma/patologia , Paraganglioma/cirurgia , Feocromocitoma/diagnóstico , Feocromocitoma/patologia , Feocromocitoma/cirurgia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia
16.
J Endocr Soc ; 4(4): bvaa018, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32190803

RESUMO

Context: Mutations to isocitrate dehydrogenase (IDH) appear to play a prognostic or predictive role in several neoplasias. Immunohistochemical staining designed to detect a specific R132H mutation to IDH1 showed expression in the normal adrenal cortex, raising interest to study the potential role of IDH1 in the pathogenesis of adrenocortical tumors. Objective: The objective of this work is to study the role of IDH1 and its mutations in adrenocortical tumors. Design and patients: IDH1 R132H immunohistological staining was performed on a cohort of 197 adrenocortical tumors. The exon of the IDH1 gene was sequenced in 16 tumors. Results: Positive IDH1 R132H immunohistochemical staining correlated with a better prognosis among patients with a malignant adrenocortical tumor. However, IDH1 R132H immunohistochemistry did not distinguish between local and metastasized tumors. We were unable to identify IDH1 mutations among our adrenocortical tumors using a targeted next-generation sequencing panel or via exon sequencing. Conclusions: Among adrenocortical carcinomas, IDH1 R132H immunopositivity correlated with a better prognosis. Thus, IDH1 R132H immunohistochemical staining could serve as a prognostic or as a potential predictive marker in adrenocortical carcinomas. Further research is needed to identify the possible alterations in IDH1 that could explain our findings, because we identified no known mutations to the IDH1 gene.

17.
JCI Insight ; 5(5)2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32161197

RESUMO

Carriers of the hydroxysteroid 17-ß dehydrogenase 13 (HSD17B13) gene variant (rs72613567:TA) have a reduced risk of NASH and cirrhosis but not steatosis. We determined its effect on liver histology, lipidome, and transcriptome using ultra performance liquid chromatography-mass spectrometry and RNA-seq. In carriers and noncarriers of the gene variant, we also measured pathways of hepatic fatty acids (de novo lipogenesis [DNL] and adipose tissue lipolysis [ATL] using 2H2O and 2H-glycerol) and insulin sensitivity using 3H-glucose and euglycemic-hyperinsulinemic clamp) and plasma cytokines. Carriers and noncarriers had similar age, sex and BMI. Fibrosis was significantly less frequent while phospholipids, but not other lipids, were enriched in the liver in carriers compared with noncarriers. Expression of 274 genes was altered in carriers compared with noncarriers, consisting predominantly of downregulated inflammation-related gene sets. Plasma IL-6 concentrations were lower, but DNL, ATL and hepatic insulin sensitivity were similar between the groups. In conclusion, carriers of the HSD17B13 variant have decreased fibrosis and expression of inflammation-related genes but increased phospholipids in the liver. These changes are not secondary to steatosis, DNL, ATL, or hepatic insulin sensitivity. The increase in phospholipids and decrease in fibrosis are opposite to features of choline-deficient models of liver disease and suggest HSD17B13 as an attractive therapeutic target.


Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , Cirrose Hepática/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfolipídeos/sangue , 17-Hidroxiesteroide Desidrogenases/genética , Feminino , Humanos , Resistência à Insulina , Lipidômica , Lipólise , Cirrose Hepática/sangue , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Transcriptoma
18.
Thyroid ; 30(3): 380-388, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32024448

RESUMO

Background: Familial adenomatous polyposis (FAP) is a condition typically caused by pathogenic germline mutations in the APC gene. In addition to colon polyps, individuals with FAP have a substantially increased risk of developing papillary thyroid cancer (PTC). Little is known about the events underlying this association, and the prevalence of somatic "second-hit" mutations in APC is controversial. Methods: Whole-genome sequencing was performed on paired thyroid tumor and normal DNA from 12 FAP patients who developed PTC. Somatic mutation profiles were compared with clinical characteristics and previously sequenced sporadic PTC cases. Germline variant profiling was performed to assess the prevalence of variants in genes previously shown to have a role in PTC predisposition. Results: All 12 patients harbored germline mutations in APC, consistent with FAP. Seven patients also had somatic mutations in APC, and seven patients harbored somatic mutations in KMT2D, which encodes a lysine methyl transferase. Mutation of these genes is extremely rare in sporadic PTCs. Notably, only two of the tumors harbored the somatic BRAF p.V600E mutation, which is the most common driver mutation found in sporadic PTCs. Six tumors displayed a cribriform-morular variant of PTC (PTC-CMV) histology, and all six had somatic mutations in APC. Additionally, nine FAP-PTC patients had rare germline variants in genes that were previously associated with thyroid carcinoma. Conclusions: Our data indicate that FAP-associated PTCs typically have distinct mutations compared with sporadic PTCs. Roughly half of the thyroid cancers that arise in FAP patients have somatic "second-hits" in APC, which is associated with PTC-CMV histology. Somatic BRAF p.V600E variants also occur in some FAP patients, a novel finding. We speculate that in carriers of heterozygous pathogenic mutations of tumor suppressor genes such as APC, a cooperating second-hit somatic variant may occur in a different gene such as KTM2D or BRAF, leading to differences in phenotypes. The role of germline variance in genes other than APC (9 of the 12 patients in this series) needs further research.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Liver Transpl ; 26(6): 764-773, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32034878

RESUMO

The etiology and prognosis of acute liver failure (ALF) remains unknown in a significant proportion of cases. Signs of autoimmunity may be present, but no consistent pattern has been observed. We aimed to analyze if pretransplant immunological findings, human leukocyte antigen (HLA) haplotypes, and clinical features among patients with an unknown etiology differ from those of autoimmune or other known etiologies. We also analyzed whether such signs impact posttransplant biopsy findings or complications. All adult ALF patients undergoing liver transplantation (LT) in Finland during 1987-2015 were followed to 2016. Data were collected from the LT registry, pathology database, and patient records. A total of 124 patients were included in the analysis. Study subgroups were acute autoimmune hepatitis (AIH; n = 25), known non-AIH etiology (n = 54), and unknown etiology (n = 45). The unknown etiology group differed from the known non-AIH group with regard to the following pretransplant autoimmunity-associated features: positive perinuclear anti-neutrophil cytoplasmic antibodies (36% versus 8%; P = 0.02) and higher mean immunoglobulin A (IgA; 3.2 ± 1.7 versus 2.1 ± 1.4, P = 0.006) and immunoglobulin G (IgG; 12.7 ± 4.3 versus 8.5 ± 3.6, P = 0.001). AIH-associated HLA haplotypes B8, DR3, and B8DR3 were more common in the AIH group (40%, 44%, and 36%, respectively) and in the unknown group (29%, 33%, and 29%, respectively) than in the known non-AIH group (11%, 17%, and 11%, respectively) or in the Finnish general population (17%, 18%, and 8%, respectively). However, these findings had no association with protocol biopsies, extrahepatic autoimmune diseases, or survival. Patients with ≥ 1 rejection episode had higher pretransplant IgA (3.7 ± 2.3 versus 2.6 ± 1.2; P = 0.02) and IgG (16.4 ± 10.2 versus 12.4 ± 6.8; P = 0.03) than those without rejections. Autoimmunity-associated pretransplant laboratory findings and HLA haplotypes were common in ALF of unknown etiology, but they showed minimal predictive value for posttransplant biopsy findings, clinical complications, or survival.


Assuntos
Hepatite Autoimune , Falência Hepática Aguda , Transplante de Fígado , Adulto , Autoimunidade , Biópsia , Hepatite Autoimune/diagnóstico , Humanos , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/cirurgia , Transplante de Fígado/efeitos adversos
20.
Hepatology ; 72(4): 1253-1266, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31925805

RESUMO

BACKGROUND AND AIMS: Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC). APPROACH AND RESULTS: We analyzed formalin-fixed, paraffin-embedded tumor tissue from 186 patients with PSC-BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such as TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g., HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). CONCLUSIONS: Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC shows a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.


Assuntos
Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , Colangite Esclerosante/complicações , Adolescente , Adulto , Idoso , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/terapia , Criança , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Colangiocarcinoma/terapia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Genes p53 , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto Jovem
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