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1.
N Engl J Med ; 387(22): 2045-2055, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36449420

RESUMO

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).


Assuntos
Antiparkinsonianos , Deferiprona , Quelantes de Ferro , Ferro , Doença de Parkinson , Substância Negra , Humanos , Deferiprona/administração & dosagem , Deferiprona/efeitos adversos , Deferiprona/farmacologia , Deferiprona/uso terapêutico , Ferro/análise , Ferro/metabolismo , Levodopa/uso terapêutico , Neutropenia/induzido quimicamente , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/efeitos adversos , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Substância Negra/química , Substância Negra/diagnóstico por imagem , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Progressão da Doença , Método Duplo-Cego , Administração Oral , Encéfalo/diagnóstico por imagem , Química Encefálica , Dopaminérgicos/administração & dosagem , Dopaminérgicos/efeitos adversos , Dopaminérgicos/farmacologia , Dopaminérgicos/uso terapêutico , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico
2.
J Med Genet ; 61(4): 378-384, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-37979962

RESUMO

BACKGROUND: The von Hippel-Lindau (VHL) disease is a hereditary tumour syndrome caused by germline mutations in VHL tumour suppressor gene. The identification of VHL variants requires accurate classification which has an impact on patient management and genetic counselling. METHODS: The TENGEN (French oncogenetics network of neuroendocrine tumors) and PREDIR (French National Cancer Institute network for Inherited predispositions to kidney cancer) networks have collected VHL genetic variants and clinical characteristics of all VHL-suspected patients analysed from 2003 to 2021 by one of the nine laboratories performing VHL genetic testing in France. Identified variants were registered in a locus-specific database, the Universal Mutation Database-VHL database (http://www.umd.be/VHL/). RESULTS: Here we report the expert classification of 164 variants, including all missense variants (n=124), all difficult interpretation variants (n=40) and their associated phenotypes. After initial American College of Medical Genetics classification, first-round classification was performed by the VHL expert group followed by a second round for discordant and ambiguous cases. Overall, the VHL experts modified the classification of 87 variants including 30 variants of uncertain significance that were as (likely)pathogenic variants for 19, and as likely benign for 11. CONCLUSION: Consequently, this work has allowed the diagnosis and influenced the genetic counselling of 45 VHL-suspected families and can benefit to the worldwide VHL community, through this review.


Assuntos
Neoplasias Renais , Doença de von Hippel-Lindau , Humanos , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Testes Genéticos , Predisposição Genética para Doença , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/patologia , Estudos de Associação Genética , Neoplasias Renais/genética , Mutação em Linhagem Germinativa
3.
Biol Cell ; 114(1): 32-55, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34561874

RESUMO

BACKGROUND INFORMATION: Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5-year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5-fluorouracil, irinotecan (SN-38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long-term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient-derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO. RESULTS: We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi-compartmental elimination models of oxaliplatin and SN-38. We then treated PaTa-1818x naive PDAC organoids with six cycles of 72 h-FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa-1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness. CONCLUSIONS: We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa-1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse. SIGNIFICANCE: To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Humanos , Irinotecano/uso terapêutico , Leucovorina , Organoides , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico
4.
J Med Genet ; 59(8): 785-792, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-34452955

RESUMO

BACKGROUND: SDHB is one of the major genes predisposing to paraganglioma/pheochromocytoma (PPGL). Identifying pathogenic SDHB variants in patients with PPGL is essential to the management of patients and relatives due to the increased risk of recurrences, metastases and the emergence of non-PPGL tumours. In this context, the 'NGS and PPGL (NGSnPPGL) Study Group' initiated an international effort to collect, annotate and classify SDHB variants and to provide an accurate, expert-curated and freely available SDHB variant database. METHODS: A total of 223 distinct SDHB variants from 737 patients were collected worldwide. Using multiple criteria, each variant was first classified according to a 5-tier grouping based on American College of Medical Genetics and NGSnPPGL standardised recommendations and was then manually reviewed by a panel of experts in the field. RESULTS: This multistep process resulted in 23 benign/likely benign, 149 pathogenic/likely pathogenic variants and 51 variants of unknown significance (VUS). Expert curation reduced by half the number of variants initially classified as VUS. Variant classifications are publicly accessible via the Leiden Open Variation Database system (https://databases.lovd.nl/shared/genes/SDHB). CONCLUSION: This international initiative by a panel of experts allowed us to establish a consensus classification for 223 SDHB variants that should be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis. This accurate classification of SDHB genetic variants will help to clarify the diagnosis of hereditary PPGL and to improve the clinical care of patients and relatives with PPGL.


Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/genética , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Humanos , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/patologia , Succinato Desidrogenase/genética
5.
Int J Cancer ; 150(11): 1850-1860, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35038360

RESUMO

Young individuals, aged <40 years, represent 7% of all patients with early breast cancer (EBC), most of whom receive chemotherapy. Preserving future fertility in these patients has become a major concern. This prospective study assessed ovarian function during and after chemotherapy according to patient and tumor characteristics and evaluated the outcome of controlled ovarian hyperstimulation (COH). Ovarian reserve was evaluated in terms of amenorrhea duration and by longitudinal serum anti-Müllerian hormone (AMH) level variations measured at study entry, during treatment and until 24 months thereafter. COH has been proposed for patients receiving adjuvant chemotherapy. We studied the association between clinical factors and ovarian function using Cox models and logistic regression. In this young population (age < 38 years, median = 32), 85 of 90 evaluable patients (94%) experienced chemo-induced amenorrhea, including six persistent amenorrhea and one chemotherapy-induced definitive ovarian failure. Overall, 33% of patients still had undetectable AMH values 12 months after the end of chemotherapy, although most had recovered spontaneous and regular menstrual function. No specific factor was associated with clinical or biological late ovarian dysfunction, except for age and baseline AMH value. Overall, 58 patients underwent COH. The mean number of total retrieved oocytes and metaphase II oocytes were of 11.7 and 6.9, respectively. Thus, our study confirms the importance of fertility preservation in young patients with EBC. Our findings indicate that sequential chemotherapy is associated with a higher risk of persistent amenorrhea. There was no significant association between tumor characteristics, fertility preservation or recovery of ovarian reserve.


Assuntos
Neoplasias da Mama , Preservação da Fertilidade , Reserva Ovariana , Hormônio Antimülleriano , Neoplasias da Mama/patologia , Feminino , Preservação da Fertilidade/efeitos adversos , Humanos , Ovário/patologia , Estudos Prospectivos
6.
Clin Endocrinol (Oxf) ; 97(1): 52-63, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35470446

RESUMO

INTRODUCTION: Few studies have attempted to evaluate the early efficacy of first-generation somatostatin analogues in somatotroph macroadenomas. OBJECTIVE: To investigate the short-term efficacy of primary therapy with lanreotide 120 mg at 1 and 3 months on tumour shrinkage and ophthalmologic symptoms in newly diagnosed patients with acromegaly. DESIGN AND PATIENTS: This single-centre retrospective study included 21 patients with de novo acromegaly resulting from pituitary macroadenoma, with optic chiasm compression (Grade ≤ 2) and/or cavernous sinus invasion, treated with a monthly injection of lanreotide 120 mg. Clinical, hormonal, ophthalmologic and magnetic resonance imaging scan evaluations were conducted after the first and the third months of treatment. RESULTS: Tumour volume reduction was more pronounced at 1 month; mean volume change: -31.4 ± 19.5%, p < .0001 than between the first and third month of treatment; mean volume reduction: -20.6 ± 13.4%, p = .0009. The mean volume change between baseline and the third month was - 46.4 ± 21.6, (p < .0001). A significant volume reduction (≥25%) was observed in 61.9% of individuals (13/21) at the first month. Among 14 individuals with optic chiasm compression and visual field defects, visual field normalization or improvement were observed in seven cases (50%), stabilization in four cases (28.5%), and mild worsening in three cases (21.4%) at 1 month. The decrease in growth hormone and IGF-1 serum values was significant at 1 month. CONCLUSIONS: Primary treatment with lanreotide 120 mg in patients with somatotroph macroadenomas provides early significant tumour shrinkage with rapid improvement of visual symptoms at the end of the first month in 50% of patients.


Assuntos
Acromegalia , Hormônio do Crescimento Humano , Neoplasias Hipofisárias , Acromegalia/tratamento farmacológico , Preparações de Ação Retardada/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I , Peptídeos Cíclicos , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/tratamento farmacológico , Estudos Retrospectivos , Somatostatina/análogos & derivados
7.
Am J Physiol Endocrinol Metab ; 320(4): E772-E783, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33491532

RESUMO

The alimentary limb has been proposed to be a key driver of the weight-loss-independent metabolic improvements that occur upon bariatric surgery. However, the one anastomosis gastric bypass (OAGB) procedure, consisting of one long biliary limb and a short common limb, induces similar beneficial metabolic effects compared to Roux-en-Y Gastric Bypass (RYGB) in humans, despite the lack of an alimentary limb. The aim of this study was to assess the role of the length of biliary and common limbs in the weight loss and metabolic effects that occur upon OAGB. OAGB and sham surgery, with or without modifications of the length of either the biliary limb or the common limb, were performed in Gottingen minipigs. Weight loss, metabolic changes, and the effects on plasma and intestinal bile acids (BAs) were assessed 15 days after surgery. OAGB significantly decreased body weight, improved glucose homeostasis, increased postprandial GLP-1 and fasting plasma BAs, and qualitatively changed the intestinal BA species composition. Resection of the biliary limb prevented the body weight loss effects of OAGB and attenuated the postprandial GLP-1 increase. Improvements in glucose homeostasis along with changes in plasma and intestinal BAs occurred after OAGB regardless of the biliary limb length. Resection of only the common limb reproduced the glucose homeostasis effects and the changes in intestinal BAs. Our results suggest that the changes in glucose metabolism and BAs after OAGB are mainly mediated by the length of the common limb, whereas the length of the biliary limb contributes to body weight loss.NEW & NOTEWORTHY Common limb mediates postprandial glucose metabolism change after gastric bypass whereas biliary limb contributes to weight loss.


Assuntos
Ácidos e Sais Biliares/metabolismo , Sistema Biliar/patologia , Ducto Colédoco/patologia , Derivação Gástrica/métodos , Glucose/metabolismo , Anastomose Cirúrgica/métodos , Animais , Ácidos e Sais Biliares/sangue , Sistema Biliar/metabolismo , Procedimentos Cirúrgicos do Sistema Biliar/métodos , Glicemia/metabolismo , Ducto Colédoco/metabolismo , Ducto Colédoco/cirurgia , Feminino , Modelos Animais , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Período Pós-Prandial , Distribuição Aleatória , Suínos , Porco Miniatura , Redução de Peso/fisiologia
8.
Reprod Biomed Online ; 42(5): 1023-1031, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33632656

RESUMO

RESEARCH QUESTION: Which clinical features, along with biological features, ultrasound features, or both, are the most strongly associated with either high or low anti-Müllerian hormone (AMH) levels in patients with polycystic ovary syndrome (PCOS)? DESIGN: A retrospective cross-sectional study conducted within a university-affiliated reproductive endocrinology unit in Lille, France. A total of 639 patients with PCOS according to the Rotterdam Criteria and 137 control women were included. A comparison of clinical, hormonal, metabolic and ultrasound data in patients with PCOS and controls belonging to the first (Q1) and fourth (Q4) quartiles of their respective AMH ranges (discriminant analysis) was conducted. RESULTS: In the PCOS group, patients in Q4 had higher LH levels and a more severe phenotype, but they were thinner and had lower levels of hyperinsulinaemia than patients in Q1. In the PCOS group, discriminant analysis yielded a highly significant model in which follicle number per ovary (FNPO) and serum LH were strongly and equally discriminating between Q4 and Q1 (R2 at 0.371 and 0.304, respectively, both P < 0.0001), whereas body mass index had less, although significant, effect (R2 = 0.075, P < 0.0001). In control women, discriminant analysis yielded a significant discriminant model, including only FNPO and age (R2 at 0.62 and 0.27, both P < 0.0001). CONCLUSION: High serum AMH levels are associated with high serum LH levels and more severe features of PCOS. Conversely, the effect of hyperinsulinism may be greater in patients with lower serum AMH levels, suggesting independent effects of AMH and insulin on the phenotypic expression of PCOS.


Assuntos
Hormônio Antimülleriano/sangue , Resistência à Insulina , Síndrome do Ovário Policístico/sangue , Adulto , Estudos Transversais , Feminino , Humanos , Síndrome do Ovário Policístico/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia , Adulto Jovem
9.
Reprod Biomed Online ; 41(6): 1112-1121, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33046375

RESUMO

RESEARCH QUESTION: Does the relative distribution of anti-Müllerian hormone (AMH) isoforms differ between patients depending on their body mass index (BMI) and polycystic ovary syndrome (PCOS) status in serum and follicular fluid? DESIGN: Obese and normal weight patients (PCOS [n = 70]; non-PCOS [n = 37]) were selected for this case-control study in the serum. Between 2018 and 2019, obese (n = 19) and normal weight (n = 20) women with or without PCOS who were receiving IVF treatment were included in the follicular fluid study. The bio-banked serums and follicular fluid were tested for total AMH (proAMH and AMHN,C combined) and proAMH using an automatic analyzer. The AMH prohormone index (API = [proAMH]/[total AMH]x 100) was calculated as an inverse marker of conversion of proAMH to AMHN,C, with only the latter isoform that could bind to the AMH receptor complex. RESULTS: The API was not significantly different between controls and women with PCOS, whereas obese women had a lower API compared with their normal weight counterparts. Grouping PCOS and controls, a lower API was found in obese versus normal weight women, suggesting a greater conversion of proAMH to AMHN,C. The API in the serum was significantly correlated with metabolic parameters. In the follicular fluid, API is not different between obese and normal weight women independently of PCOS and is higher than in the concomitant serum. CONCLUSIONS: The proportion of inactive form of AMH in the serum is higher in normal weight versus obese women but not in the follicular fluid, independently of PCOS. The conversion of proAMH into the cleaved isoform is likely to occur in extra-ovarian tissues and to exacerbate in obese individuals.


Assuntos
Hormônio Antimülleriano/metabolismo , Líquido Folicular/metabolismo , Obesidade/metabolismo , Síndrome do Ovário Policístico/metabolismo , Adolescente , Adulto , Hormônio Antimülleriano/sangue , Hormônio Antimülleriano/química , Biomarcadores/sangue , Biomarcadores/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Líquido Folicular/química , França/epidemiologia , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/epidemiologia , Isoformas de Proteínas/análise , Isoformas de Proteínas/sangue , Isoformas de Proteínas/metabolismo , Precursores de Proteínas/sangue , Precursores de Proteínas/metabolismo , Adulto Jovem
10.
J Med Genet ; 56(8): 513-520, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30877234

RESUMO

BACKGROUND: Knowing the genetic status of patients affected by paragangliomas and pheochromocytomas (PPGL) is important for the guidance of their management and their relatives. Our objective was to improve the diagnostic performances of PPGL genetic testing by next-generation sequencing (NGS). METHODS: We developed a custom multigene panel, which includes 17 PPGL genes and is compatible with both germline and tumour DNA screening. The NGS assay was first validated in a retrospective cohort of 201 frozen tumour DNAs and then applied prospectively to 623 DNAs extracted from leucocytes, frozen or paraffin-embedded PPGL tumours. RESULTS: In the retrospective cohort, the sensitivity of the NGS assay was evaluated at 100% for point and indels mutations and 86% for large rearrangements. The mutation rate was re-evaluated from 65% (132/202) to 78% (156/201) after NGS analysis. In the prospective cohort, NGS detected not only germline and somatic mutations but also co-occurring variants and mosaicism. A mutation was identified in 74% of patients for whom both germline and tumour DNA were available. CONCLUSION: The analysis of 824 DNAs from patients with PPGL demonstrated that NGS assay significantly improves the performances of PPGL genetic testing compared with conventional methods, increasing the rate of identified mutations and identifying rare genetic mechanisms.


Assuntos
Biomarcadores Tumorais , Predisposição Genética para Doença , Paraganglioma/genética , Feocromocitoma/genética , Alelos , Estudos de Associação Genética , Testes Genéticos/métodos , Testes Genéticos/normas , Variação Genética , Genótipo , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Análise de Sequência de DNA
11.
Reprod Biomed Online ; 39(1): 141-148, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31036431

RESUMO

RESEARCH QUESTION: An association has been found between high anti-Müllerian hormone (AMH) levels during pregnancy and the development of polycystic ovary syndrome (PCOS)-like phenotypic traits in mouse offspring. The aim of this study was to determine whether AMH levels are associated with maternal testosterone levels, and whether high AMH concentration influences the risk of developing PCOS-related adverse pregnancy outcomes. DESIGN: Maternal serum AMH, testosterone and sex hormone binding globulin levels were measured in blood samples taken in early second-trimester pregnancies from women with PCOS (n = 159) and healthy controls matched for body mass index (n = 320). Possible associations with preeclampsia, gestational hypertension, gestational diabetes, preterm birth and birthweight was explored by logistic and linear regression models. RESULTS: Women with PCOS had higher AMH, higher total testosterone levels and higher free androgen index than controls (P < 0.001 for all three parameters). Among women with PCOS, high testosterone levels (B = 2.7; ß = 0.26; P = 0.001) and low first trimester body mass index (B = -0.5; ß = -0.17; P = 0.043) remained independently associated with AMH. High AMH levels were associated with decreased risk of gestational hypertension (adjusted OR 0.55; 95% CI 0.34 to 0.87), but no association was found with other adverse pregnancy outcomes or birthweight. CONCLUSIONS: Women with PCOS had higher AMH levels during pregnancy compared with controls, but high AMH was not associated with increased risk of adverse pregnancy outcomes or birthweight.


Assuntos
Hormônio Antimülleriano/sangue , Doenças do Recém-Nascido/diagnóstico , Síndrome do Ovário Policístico/diagnóstico , Complicações na Gravidez/diagnóstico , Segundo Trimestre da Gravidez/sangue , Adulto , Peso ao Nascer , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/epidemiologia , Doenças do Recém-Nascido/etiologia , Hormônio Luteinizante/sangue , Complicações do Trabalho de Parto/diagnóstico , Complicações do Trabalho de Parto/epidemiologia , Complicações do Trabalho de Parto/etiologia , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/etiologia , Suécia/epidemiologia , Testosterona/sangue
12.
Reprod Biomed Online ; 36(6): 711-718, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29523398

RESUMO

The relationship between early recovery of menstrual activity and blood anti-Müllerian hormone (AMH) concentrations were investigated within the first year post-chemotherapy in 32 young patients with breast cancer. All were treated by surgery and the same chemotherapy protocol (three cycles of FEC100 plus three cycles of taxanes). Menstrual activity, blood AMH (using picoAMH ELISA) and FSH concentrations were measured longitudinally before, during and up to 12 months after the end of chemotherapy (six samples per patient). Among the cohort, 17 patients recovered spontaneous cycles at +6 months (fast recovery) whereas the remaining 15 patients were still amenorrheic at that time (slow recovery). Blood AMH differed between these two subgroups at each time of the recovery phase starting at 3 months post-chemotherapy. The AMH patterns were also different: rapid and large increase in the fast recovery versus slow and partial increase in the slow recovery subgroup. No difference in ovarian recovery was observed between patients with a hormone positive or negative tumour. In conclusion, studying the post-chemotherapy patterns of menstrual activity and AMH, two paces of early ovarian recovery are distinguishable in young breast cancer patients who received the same chemotherapy protocol. This suggests different individual ovarian susceptibilities to chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Ovário/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Adulto , Hormônio Antimülleriano/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores/sangue , Neoplasias da Mama/patologia , Feminino , Humanos , Reserva Ovariana , Ovário/patologia
13.
Int J Mol Sci ; 19(3)2018 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-29495341

RESUMO

Functional specialization of cells and tissues in metazoans require specific gene expression patterns. Biological processes, thus, need precise temporal and spatial coordination of gene activity. Regulation of the fate of messenger RNA plays a crucial role in this context. In the present review, the current knowledge related to the role of RNA-binding proteins in the whole mRNA life-cycle is summarized. This field opens up a new angle for understanding the importance of the post-transcriptional control of gene expression in cancer cells. The emerging role of non-classic RNA-binding proteins is highlighted. The goal of this review is to encourage readers to view, through the mRNA life-cycle, novel aspects of the molecular basis of cancer and the potential to develop RNA-based therapies.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Estabilidade de RNA , RNA Mensageiro/genética , Animais , Humanos , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/terapia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Processamento Pós-Transcricional do RNA , Splicing de RNA , Transporte de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transcrição Gênica
14.
Hum Reprod ; 32(8): 1716-1722, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28854589

RESUMO

STUDY QUESTION: Does the use of the serum anti-Müllerian hormone (AMH) assay to replace or complement ultrasound (U/S) affect the diagnosis or phenotypic distribution of polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Combining U/S and the serum AMH assay to define polycystic ovarian morphology (PCOM) diagnoses PCOS (according to the Rotterdam classification) in more patients than definitions using one or the other of these indicators exclusively. WHAT IS KNOWN ALREADY: Since 2003, PCOM, as defined by U/S, is one of the three diagnostic criteria for PCOS. As it is closely correlated with follicle excess seen at U/S, an excessive serum AMH level could be used as a surrogate for PCOM. STUDY DESIGN, SIZE, DURATION: Single-center retrospective study from a database of prospectively collected clinical, laboratory and ultrasound data from patients referred for oligo-anovulation (OA) and/or hyperandrogenism (HA) between January 2009 and January 2016. PARTICIPANTS/MATERIALS, SETTING, METHOD: The standard Rotterdam classification for PCOS was tested against two modified versions that defined PCOM by either excessive serum AMH level alone (AMH-only) or a combination (i.e. 'and/or') of the latter and U/S. The PCOS phenotypes were defined as A (full phenotype, OA+HA+PCOM), B (OA+HA), C (HA+PCOM) and D (OA+PCOM). MAIN RESULTS AND THE ROLE OF CHANCE: PCOS was more frequently diagnosed when PCOM was defined as the combination 'positive U/S' and/or 'positive AMH' (n = 639) than by either only U/S-only (standard definition, n = 612) or by AMH-only (n = 601). With this combination, PCOM was recognized in 637 of the 639 cases that met the Rotterdam classification, and phenotype B practically disappeared. In this population, U/S and AMH markers were discordant for PCOM in 103 (16.1%) cases (9% U/S-only, 7.1% AMH-only, P = 0.159). The markers used had no other significant impact on the phenotypic distribution (except for phenotype B). However, the percentage of cases positive by U/S-only was significantly higher in phenotype D than in phenotype A (14.1% vs. 5.8%, P < 0.05). Furthermore, in the discordant cases, plasma LH levels were significantly higher in the AMH-only group than in the concordant cases, and fasting insulin serum levels tended to be higher in the U/S-only group. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study. A referral bias explains the relatively high proportion of patients with phenotype D (28%). PCOM was defined by in-house thresholds. The AMH assay used is no longer commercially available. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that ideally both U/S data and serum AMH level should be integrated to define PCOM in the Rotterdam classification. In a cost-effectiveness approach, the choice of one or the other has little impact on the diagnosis and the phenotyping of PCOS. STUDY FUNDING/COMPETING INTEREST(S): No external funding. The authors have no conflict of interest to declare.


Assuntos
Hormônio Antimülleriano/sangue , Ovário/diagnóstico por imagem , Síndrome do Ovário Policístico/diagnóstico , Adulto , Feminino , Humanos , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/classificação , Estudos Retrospectivos , Ultrassonografia , Adulto Jovem
15.
Hum Reprod ; 32(8): 1710-1715, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28854583

RESUMO

STUDY QUESTION: Can anti-Müllerian hormone (AMH) automated immunoassays (Elecsys® and Access) be used interchangeably as a companion diagnostic for individualisation of follitropin delta dosing? SUMMARY ANSWER: The Access assay gives systematically higher AMH values than the Elecsys® assay which results in over 29% of women being misclassified to a different follitropin delta dose. WHAT IS KNOWN ALREADY: Follitropin delta is the first gonadotrophin to be licenced with a companion diagnostic, the Roche Elecsys® AMH Plus assay. Alternative automated AMH assays including the Beckman Coulter Access immunoassay are considered to provide similar results, but clarification of their suitability as an off-licence companion diagnostic for follitropin delta is required. STUDY DESIGN, SIZE, DURATION: We systematically searched the existing literature for studies that had measured AMH using both automated assays in the same cohort of women. Individual paired patient data were acquired from each author and combined with unpublished data. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified five eligible prospective published studies and one additional unpublished study. A 100% response from the authors was achieved. We collected paired AMH data on samples from 848 women. Passing-Bablok regression and Bland-Altman plots were used to compare the analytical performance of the two assays. The degree of misclassification to different treatment categories was estimated should the Access AMH be used as a companion diagnostic instead of the Elecsys AMH in determining the dosing of follitropin delta. MAIN RESULTS AND THE ROLE OF CHANCE: The Passing-Bablok regression shows a linear relationship (Access = -0.05 + 1.10 × Elecsys). The Access assay systematically gave higher values by an average of 10% compared with the Elecsys assay (slope = 1.10, 95% CI: 1.09 to 1.12). The average of the difference between the two assays was 2.7 pmol/l. The 95% limits of agreement were -11.7 to 6.3. Overall 253 (29.3%) women would have received an inappropriate follitropin delta dose if the Beckman Coulter Access assay was used. Specifically, a substantial proportion of women (ranging from 49% to 90% depending on the AMH category) would receive a lower dose of follitropin delta based on the Access AMH assay. Up to 10% (ranging from 2.5% to 10%) of women with high ovarian reserve would have been misclassified to a greater dose of follitropin delta based on the Access AMH assay. LIMITATIONS REASONS FOR CAUTION: We compared the values of the two principal automated assays, extrapolation of our findings to other automated AMH assays would require similar comprehensive examination. WIDER IMPLICATIONS OF THE FINDINGS: An international standard for the calibration of the automated AMH assays is warranted to facilitate efficient use of AMH as a companion diagnostic. The variable calibration of alternative automated AMH assays may adversely impact on the performance of the follitropin delta dosing algorithm. STUDY FUNDING/COMPETING INTEREST(S): No formal funding has been received for this study. SI is funded by a UK Medical Research Council skills development fellowship (MR/N015177/1). SMN has received speakers fees, travel to meetings and participated in advisory Boards for Beckman Coulter, IBSA, Ferring Pharmaecuticals, Finox, Merck Serono, Merck and Roche Diagnostics. SMN has received research support from Ansh laboratories, Beckman Coulter, Ferring Pharmaceuticals and Roche Diagnostics. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Hormônio Antimülleriano/sangue , Hormônio Foliculoestimulante Humano/administração & dosagem , Imunoensaio/métodos , Infertilidade Feminina/terapia , Adulto , Relação Dose-Resposta a Droga , Feminino , Hormônio Foliculoestimulante Humano/uso terapêutico , Humanos , Infertilidade Feminina/sangue , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico
16.
Reprod Biomed Online ; 35(3): 325-330, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28624344

RESUMO

The relationship between serum anti-Müllerian hormone (AMH) levels, body mass index (BMI) and related metabolic factors were investigated in women with polycystic ovary syndrome (PCOS). A total of 691 women aged between 18 and 35 years, referred to the Department of Gynaecological Endocrinology at the University Hospital of Lille between 2009 and 2014 were included: 137 controls and 554 women with PCOS. Mean serum AMH levels were slightly but significantly lower in women with PCOS who were overweight or obese (BMI ≥25) compared with women of normal weight (BMI <25) (P < 0.05). No such difference was found in the control group. After bivariate analysis, no significant correlation was found between BMI and AMH in controls. In the PCOS group, this relationship was significant (P = 0.0001) but weak (r = -0.177). Stepwise multiple regression analysis yielded a significant model, including five variables (follicle count, serum androstenedione, BMI, serum LH and FSH) explaining 38.6%, 3.4%, 1.4%, 0.7% and 1.4% of the total serum AMH variance, respectively. No effect of metabolic status was found on serum AMH levels in controls, but a significant, albeit weak, negative independent correlation was found between AMH and BMI in women with PCOS.


Assuntos
Hormônio Antimülleriano/sangue , Obesidade/complicações , Obesidade/metabolismo , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Infertilidade Feminina/sangue , Infertilidade Feminina/etiologia , Reserva Ovariana/fisiologia , Sobrepeso/complicações , Sobrepeso/metabolismo , Adulto Jovem
17.
Pancreatology ; 16(1): 115-20, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26613889

RESUMO

BACKGROUND/OBJECTIVES: CA 19-9 is the gold standard biomarker of pancreatic adenocarcinoma despite several weaknesses in particular a high rate of false positives or negatives. CA-125 corresponding to MUC16 and galectin-3, a lectin able to interact with mucin-associated carbohydrates, are tumor-associated proteins. We investigated whether combined measurement of CA 19-9, galectin-3 and CA-125 may help to better discriminate pancreatic adenocarcinoma versus non-malignant pancreatic diseases. METHODS: We evaluated by immunohistochemistry the expression of MUC4, MUC16 (CA-125) and galectin-3 in 31 pancreatic adenocarcinomas. We measured CA 19-9, CA-125 and Gal-3 in the serum from patients with pancreatic benign diseases (n = 58) or adenocarcinoma (n = 44). Clinical performance of the 3 biomarkers for cancer diagnosis and prognosis was analyzed. RESULTS: By immunohistochemistry, MUC16 and Gal-3 were expressed in 74% and 84% of adenocarcinomas versus 0% and 3.2% in peri-tumoral regions, respectively. At the serum level, CA 19-9 and CA125 were significantly higher in patients with pancreatic adenocarcinoma whereas Gal-3 levels did not differ. The performance of CA 19-9 for cancer detection was higher than those of CA-125 or Gal-3 by ROC analysis. However, CA-125 offers the highest specificity for malignancy (81%) because of an absence of false positives among type 2 diabetic patients. Cancer deaths assessed 6 or 12 months after diagnosis varied according to the initial CA-125 level (p < 0.006). CONCLUSION: Gal-3 is not an interesting biomarker for pancreatic adenocarcinoma detection. CA 19-9 alone exhibits the best performance but measuring CA-125 provides complementary information in terms of diagnosis and prognosis.


Assuntos
Antígeno Ca-125/metabolismo , Antígeno CA-19-9/metabolismo , Galectina 3/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Sanguíneas , Antígeno Ca-125/sangue , Antígeno Ca-125/genética , Antígeno CA-19-9/sangue , Antígeno CA-19-9/genética , Feminino , Galectina 3/sangue , Galectina 3/genética , Galectinas , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mucina-4/genética , Mucina-4/metabolismo , Análise de Sobrevida
19.
Ann Endocrinol (Paris) ; 85(4): 276-283, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38815921

RESUMO

CONTEXT: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors with high heritability, justifying systematic genetic screening for a germline variant in one of the twenty predisposing genes described to date. PURPOSE: To describe the experience of one endocrine oncogenetic laboratory over a period of 21 years (2001-2022), from the beginning of PPGL genotyping with Sanger sequencing in 2001 to the implementation of next-generation sequencing (NGS). METHOD: The activity database of an academic oncogenetic laboratory was searched to extract patients/relatives identified with a pathogenic variant/likely pathogenic variant (PV/LPV) over a period of 21 years. Clinical and genetic data were compared. RESULTS: In total, 606 index cases with PPGL and 444 relatives were genotyped. Genotyping of index cases was performed by Sanger sequencing and gene deletion analysis in 327 cases and by NGS in 279. Germline PV/LPV spanning 10 genes was identified in 165 index cases (27.2%). Several recurrent PV/LPVs in SDHx were observed in non-related index cases, the most frequent being SDHD, c.170-1G>T (n=28). This subgroup showed great phenotypic variability both between and within families in terms of both tumor location and number. Four patients (1.1%) with PV/LPV in SDHx had 3PA (Pituitary Adenoma and pheochromocytoma/paraganglioma) syndrome. 258 relatives (58.1%) had inherited a PV/LPV in one driver gene. The rate of PV/LPV carriers who were symptomatic at first imaging evaluation was 32%, but varied between<20% in SDHB and SDHC and >50% in SDHD, VHL and MAX. CONCLUSION: Our experience confirmed previously established genotype-phenotype correlations, but also highlights atypical clinical presentations, even for the same genetic variant. These data must be taken into account for optimal patient follow-up and management.


Assuntos
Neoplasias das Glândulas Suprarrenais , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/genética , Feocromocitoma/epidemiologia , Paraganglioma/genética , Paraganglioma/epidemiologia , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/epidemiologia , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Testes Genéticos , Idoso , Sequenciamento de Nucleotídeos em Larga Escala , Criança , Genótipo , Succinato Desidrogenase/genética
20.
Eur Heart J ; 33(2): 191-202, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21719456

RESUMO

BACKGROUND: Recent studies have demonstrated that aldosterone levels measured in patients with heart failure or acute myocardial infarction (MI) are associated with long-term mortality, but the association with aldosterone levels in patients with coronary artery disease (CAD) outside these specific settings remains unknown. In addition, no clear mechanism has been elucidated to explain these observations. The present study was designed to evaluate the relationship between the level of aldosterone and the risk of death and acute ischaemic events in CAD patients with a preserved left ventricular (LV) function and no acute MI. METHODS AND RESULTS: In 799 consecutive CAD patients referred for elective coronary angioplasty measurements were obtained before the procedure for: aldosterone (median = 25 pg/mL), brain natriuretic peptide (BNP) (median = 35 pg/mL), hsC-reactive protein (median = 4.17 mg/L), and left ventricular ejection fraction (mean = 58%). Patients with acute MI or coronary syndrome (ACS) who required urgent revascularization were not included in the study. The primary endpoint, cardiovascular death, occurred in 41 patients during a median follow-up period of 14.9 months. Secondary endpoints-total mortality, acute ischaemic events (acute MI or ischaemic stroke), and the composite of death and acute ischaemic events-were observed in 52, 54, and 94 patients, respectively. Plasma aldosterone was found to be related to BMI, hypertension and NYHA class, and inversely related to age, creatinine clearance, and use of beta-blockers. Multivariate Cox model analysis demonstrated that aldosterone was independently associated with cardiovascular mortality (P = 0.001), total mortality (P = 0.001), acute ischaemic events (P = 0.01), and the composite of death and acute ischaemic events (P = 0.004). Reclassification analysis, using integrated discrimination improvement (IDI) and net reclassification improvement (NRI), demonstrated incremental predictive value of aldosterone (P < 0.0001). CONCLUSION: Our results demonstrate that, in patients with CAD but without heart failure or acute MI, the level of aldosterone is strongly and independently associated with mortality and the occurrence of acute ischaemic events.


Assuntos
Aldosterona/metabolismo , Doença da Artéria Coronariana/sangue , Fatores Etários , Idoso , Angioplastia Coronária com Balão/mortalidade , Índice de Massa Corporal , Isquemia Encefálica/sangue , Isquemia Encefálica/mortalidade , Isquemia Encefálica/fisiopatologia , Proteína C-Reativa/metabolismo , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/fisiopatologia , Creatinina/metabolismo , Morte Súbita Cardíaca , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/sangue , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Peptídeo Natriurético Encefálico/metabolismo , Valor Preditivo dos Testes , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/fisiopatologia , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia
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