RESUMO
STUDY QUESTION: How do plasma progesterone (P) and dydrogesterone (D) concentrations together with endometrial histology, transcriptomic signatures, and immune cell composition differ when oral dydrogesterone (O-DYD) or micronized vaginal progesterone (MVP) is used for luteal phase support (LPS)? SUMMARY ANSWER: Although after O-DYD intake, even at steady-state, plasma D and 20αdihydrodydrogesterone (DHD) concentrations spiked in comparison to P concentrations, a similar endometrial signature was observed by histological and transcriptomic analysis of the endometrium. WHAT IS KNOWN ALREADY: O-DYD for LPS has been proven to be noninferior compared to MVP in two phase III randomized controlled trials. Additionally, a combined individual participant data and aggregate data meta-analysis indicated that a higher pregnancy rate and live birth rate may be obtained in women receiving O-DYD versus MVP for LPS in fresh IVF/ICSI cycles. Little data are available on the pharmacokinetic (PK) profiles of O-DYD versus MVP and their potential molecular differences at the level of the reproductive organs, particularly at the endometrial level. STUDY DESIGN, SIZE, DURATION: Thirty oocyte donors were planned to undergo two ovarian stimulation (OS) cycles with dual triggering (1.000 IU hCG + 0.2 mg triptorelin), each followed by 1 week of LPS: O-DYD or MVP, in a randomized, cross-over, double-blind, double-dummy fashion. On both the first and eighth days of LPS, serial blood samples upon first dosing were harvested for plasma D, DHD, and P concentration analyses. On Day 8 of LPS, an endometrial biopsy was collected for histologic examination, transcriptomics, and immune cell analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: All oocyte donors were <35 years old, had regular menstrual cycles, no intrauterine contraceptive device, anti-Müllerian hormone within normal range and a BMI ≤29 kg/m2. OS was performed on a GnRH antagonist protocol followed by dual triggering (1.000 IU hCG + 0.2 mg triptorelin) as soon as ≥3 follicles of 20 mm were present. Following oocyte retrieval, subjects initiated LPS consisting of MVP 200 mg or O-DYD 10 mg, both three times daily. D, DHD, and P plasma levels were measured using liquid chromatography-tandem mass spectrometry. Histological assessment was carried out using the Noyes criteria. Endometrial RNA-sequencing was performed for individual biopsies and differential gene expression was analyzed. Endometrial single-cell suspensions were created followed by flow cytometry for immune cell typing. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 21 women completed the entire study protocol. Subjects and stimulation characteristics were found to be similar between groups. Following the first dose of O-DYD, the average observed maximal plasma concentrations (Cmax) for D and DHD were 2.9 and 77 ng/ml, respectively. The Cmax for D and DHD was reached after 1.5 and 1.6 h (=Tmax), respectively. On the eighth day of LPS, the first administration of that day gave rise to a Cmax of 3.6 and 88 ng/ml for D and DHD, respectively. For both, the observed Tmax was 1.5 h. Following the first dose of MVP, the Cmax for P was 16 ng/ml with a Tmax of 4.2 h. On the eighth day of LPS, the first administration of that day showed a Cmax for P of 21 ng/ml with a Tmax of 7.3 h. All 42 biopsies showed endometrium in the secretory phase. The mean cycle day was 23.9 (±1.2) in the O-DYD group versus 24.0 (±1.3) in the MVP group. RNA-sequencing did not reveal significantly differentially expressed genes between samples of both study groups. The average Euclidean distance between samples following O-DYD was significantly lower than following MVP (respectively 12.1 versus 18.8, Mann-Whitney P = 6.98e-14). Immune cell profiling showed a decrease of CD3 T-cell, γδ T-cell, and B-cell frequencies after MVP treatment compared to O-DYD, while the frequency of natural killer (NK) cells was significantly increased. LIMITATIONS, REASONS FOR CAUTION: The main reason for caution is the small sample size, given the basic research nature of the project. The plasma concentrations are best estimates as this was not a formal PK study. Whole tissue bulk RNA-sequencing has been performed not correcting for bias caused by different tissue compositions across biopsies. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study comparing O-DYD/MVP, head-to-head, in a randomized design on a molecular level in IVF/ICSI. Plasma serum concentrations suggest that administration frequency is important, in addition to dose, specifically for O-DYD showing a rapid clearance. The molecular endometrial data are overall comparable and thus support the previously reported noninferior reproductive outcomes for O-DYD as compared to MVP. Further research is needed to explore the smaller intersample distance following O-DYD and the subtle changes detected in endometrial immune cells. STUDY FUNDING/COMPETING INTEREST(S): Not related to this work, C.Bl. has received honoraria for lectures, presentations, manuscript writing, educational events, or scientific advice from Abbott, Ferring, Organon, Cooper Surgical, Gedeon-Richter, IBSA, and Merck. H.T. has received honoraria for lectures, presentations, manuscript writing, educational events, or scientific advice from Abbott, Ferring, Cooper Surgical, Gedeon-Richter, Cook, and Goodlife. S.M. has received honoraria for lectures, presentations, educational events, or scientific advice from Abbott, Cooper Surgical, Gedeon-Richter, IBSA, and Merck and Oxolife. G.G. has received honoraria for lectures, presentations, educational events, or scientific advice from Merck, MSD, Organon, Ferring, Theramex, Gedeon-Richter, Abbott, Biosilu, ReprodWissen, Obseva, PregLem, Guerbet, Cooper, Igyxos, and OxoLife. S.V.-S. is listed as inventor on two patents (WO2019115755A1 and WO2022073973A1), which are not related to this work. TRIAL REGISTRATION NUMBER: EUDRACT 2018-000105-23.
Assuntos
Didrogesterona , Progesterona , Gravidez , Humanos , Feminino , Adulto , Estudos Cross-Over , Pamoato de Triptorrelina , Fase Luteal , Lipopolissacarídeos , Injeções de Esperma Intracitoplásmicas/métodos , Taxa de Gravidez , Indução da Ovulação/métodos , Endométrio , RNA , Fertilização in vitro/métodos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
STUDY QUESTION: Does an early proliferative phase endometrial biopsy harvested during ovarian stimulation harbour information predictive of the outcome following fresh embryo transfer (ET) in that same cycle? SUMMARY ANSWER: Transcriptome analysis of the whole-tissue endometrium did not reveal significant differential gene expression (DGE) in relation to the outcome; however, the secretome profile of isolated, cultured and in vitro decidualized endometrial stromal cells (EnSCs) varied significantly between patients who had a live birth compared to those with an implantation failure following fresh ET in the same cycle as the biopsy. WHAT IS KNOWN ALREADY: In the majority of endometrial receptivity research protocols, biopsies are harvested during the window of implantation (WOI). This, however, precludes ET in that same cycle, which is preferable as the endometrium has been shown to adapt over time. Endometrial biopsies taken during ovarian stimulation have been reported not to harm the chances of implantation, and in such biopsies DGE has been observed between women who achieve pregnancy versus those who do not. The impact of the endometrial proliferative phase on human embryo implantation remains unclear, but deserves further attention, especially since in luteal phase endometrial biopsies, a transcriptional signature predictive for repeated implantation failure has been associated with reduced cell proliferation, possibly indicating proliferative phase involvement. Isolation, culture and in vitro decidualization (IVD) of EnSCs is a frequently applied basic research technique to assess endometrial functioning, and a disordered EnSC secretome has previously been linked with failed implantation. STUDY DESIGN, SIZE, DURATION: This study was nested in a randomized controlled trial (RCT) investigating the effect of endometrial scratching during the early follicular phase of ovarian stimulation on clinical pregnancy rates after IVF/ICSI. Of the 96 endometrial biopsies available, after eliminating those without fresh ET and after extensive matching in order to minimize the risk of potential confounding, 18 samples were retained to study two clinical groups: nine biopsies of patients with a live birth versus nine biopsies of patients with an implantation failure, both following fresh ET performed in the same cycle as the biopsy. We studied the proliferative endometrium by analysing its transcriptome and by isolating, culturing and decidualizing EnSCs in vitro. We applied this latter technique for the first time on proliferative endometrial biopsies obtained during ovarian stimulation for in-cycle outcome prediction, in an attempt to overcome inter-cycle variability. PARTICIPANTS/MATERIALS, SETTING, METHODS: RNA-sequencing was performed for 18 individual whole-tissue endometrial biopsies on an Illumina HiSeq1500 machine. DGE was analysed three times using different approaches (DESeq2, EdgeR and the Wilcoxon rank-sum test, all in R). EnSC isolation and IVD was performed (for 2 and 4 days) for a subset of nine samples, after which media from undifferentiated and decidualized cultures were harvested, stored at -80°C and later assayed for 45 cytokines using a multiplex suspension bead immunoassay. The analysis was performed by partial least squares regression modelling. MAIN RESULTS AND THE ROLE OF CHANCE: After correction for multiple hypothesis testing, DGE analysis revealed no significant differences between endometrial samples from patients who had a live birth and those with an implantation failure following fresh ET. However secretome analysis after EnSC isolation and culture, showed two distinct clusters that clearly corresponded to the two clinical groups. Upon IVD, the secretome profiles shifted from that of undifferentiated cells but the difference between the two clinical groups remained yet were muted, suggesting convergence of cytokine profiles after decidualization. LIMITATIONS, REASONS FOR CAUTION: Caution is warranted due to the limited sample size of the study and the in vitro nature of the EnSC experiment. Validation on a larger scale is necessary, however, hard to fulfil given the very limited availability of in-cycle proliferative endometrial biopsies outside a RCT setting. WIDER IMPLICATIONS OF THE FINDINGS: These data support the hypothesis that the endometrium should be assessed not only during the WOI and that certain endometrial dysfunctionalities can probably be detected early in a cycle by making use of the proliferative phase. This insight opens new horizons for the development of endometrial tests, whether diagnostic or predictive of IVF/ICSI treatment outcome. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Fonds Wetenschappelijk Onderzoek (FWO, Flanders, Belgium, 11M9415N, 1 524 417N), Wetenschappelijk Fonds Willy Gepts (WFWG G160, Universitair Ziekenhuis Brussel, Belgium) and the National Medicine Research Council (NMRC/CG/M003/2017, Singapore). There are no conflicts of interests. TRIAL REGISTRATION NUMBER: NCT02061228.
Assuntos
Transferência Embrionária , Injeções de Esperma Intracitoplásmicas , Bélgica , Endométrio , Feminino , Humanos , Gravidez , SingapuraRESUMO
Cervical intra-epithelial neoplasia is a very common and well-known pathology. However superficial spreading of this lesion is very rare. The authors present a case of a 72-year-old woman with an abdominal mass, who had previously undergone a cervical conisation for a high-grade cervical intra-epithelial neoplasia. Anatomo-pathological examination of the mass showed a large distended fluid-filled uterus with the entire endometrium replaced by a high-grade squamous cell lesion. There were only micro-invasive foci found. The authors performed a literature search in PubMed with the following MeSH-terms: "squamous cell carcinoma" and "endometrium". Other articles were selected out of the references of previously found articles. Only 31 similar cases were found. The presentation of the cases is varies extremely and a long-term prognosis is not yet known.
Assuntos
Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/patologia , Idoso , Feminino , HumanosRESUMO
The use of a gonadotrophin-releasing hormone (GnRH) agonist to trigger final oocyte maturation in a GnRH antagonist protocol has been associated with poorer clinical outcomes due to an increased luteal-phase defect. It has been shown that LH activity is crucial in a normal luteal phase. Studies assessing the LH concentrations after clomiphene citrate co-treatment have observed increased luteal-phase LH concentrations. The purpose of this prospective cohort study was to analyse the effect of clomiphene citrate on the endocrine profile in the luteal phase when using GnRH agonist trigger. This was evaluated in eight oocyte donors undergoing ovarian stimulation using clomiphene citrate in combination with recombinant FSH compared with a control group of five donors treated with recombinant FSH only. The endocrine profile was comparable in both groups, except for serum LH concentrations on the day after trigger (121.3±53.0IU/l versus 52.9±21.5IU/l, respectively, P=0.022). No significant differences in LH concentrations were found on the day of trigger or 5days after oocyte retrieval. In conclusion, a luteal-phase defect was observed despite treatment with clomiphene citrate during ovarian stimulation. The use of gonadotrophin-releasing hormone (GnRH) agonist to trigger ovulation in IVF has been associated with poorer pregnancy outcomes due to an increased luteal-phase defect. The luteal phase is the last phase of the menstrual cycle and is defined as the period between ovulation and the beginning of pregnancy or menses. It has been shown the activity of LH is crucial in a normal luteal phase. Studies assessing the LH concentrations after clomiphene citrate, an oestrogen receptor inhibitor, co-treatment have observed increased luteal-phase LH concentrations. The purpose of this prospective cohort study was to analyse the effect of clomiphene citrate on menstrual cycle day 2-6 on the hormone profile in the luteal phase when using GnRH agonist trigger. This was evaluated was in eight oocyte donors undergoing ovarian stimulation using recombinant FSH compared with a control cohort of donors treated with recombinant FSH only. The current prospective cohort study reports higher LH concentrations on the day after GnRH agonist trigger, but not 5days after oocyte retrieval (i.e. in the luteal phase). In conclusion, a luteal-phase defect was observed despite the administration of clomiphene citrate during ovarian stimulation. Additional treatment with clomiphene citrate in the follicular phase is therefore not a valid alternative to prevent luteal-phase defect after GnRH agonist trigger.
Assuntos
Clomifeno/uso terapêutico , Hormônio Foliculoestimulante/uso terapêutico , Hormônio Liberador de Gonadotropina/uso terapêutico , Fase Luteal/efeitos dos fármacos , Indução da Ovulação/métodos , Adulto , Clomifeno/administração & dosagem , Estudos de Coortes , Endométrio/efeitos dos fármacos , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/administração & dosagem , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/administração & dosagem , Humanos , Hormônio Luteinizante/sangue , Progesterona/sangueRESUMO
STUDY QUESTION: Do differences in endometrial gene expression exist after ovarian stimulation with four different regimens of triggering final oocyte maturation and luteal phase support in the same patient? SUMMARY ANSWER: Significant differences in the expression of genes involved in receptivity and early implantation were seen between the four protocols. WHAT IS KNOWN ALREADY: GnRH agonist triggering is an alternative to hCG triggering in GnRH antagonist co-treated cycles, resulting in an elimination of early ovarian hyperstimulation syndrome. Whereas previous studies have revealed a low ongoing clinical pregnancy rate after GnRH agonist trigger due to a high early pregnancy loss rate, despite supplementation with the standard luteal phase support, more recent studies, employing a 'modified' luteal phase support including a bolus of 1500 IU hCG on the day of oocyte aspiration, have reported ongoing pregnancy rates similar to those seen after hCG triggering. STUDY DESIGN, SIZE DURATION: A prospective randomized study was performed in four oocyte donors recruited from an oocyte donation program during the period 2010-2011. PARTICIPANTS, MATERIALS, SETTING, METHODS: Four oocyte donors in a university IVF center each prospectively underwent four consecutive stimulation protocols, with different modes of triggering final oocyte maturation and a different luteal phase support, followed by endometrial biopsy on Day 5 after oocyte retrieval. The following protocols were used: (A) 10 000 IU hCG and standard luteal phase support, (B) GnRH agonist (triptorelin 0.2 mg), followed by 1500 IU hCG 35 h after triggering final oocyte maturation, and standard luteal phase support, (C) GnRH agonist (triptorelin 0.2 mg) and standard luteal phase support and (D) GnRH agonist (triptorelin 0.2 mg) without luteal phase support. Microarray data analysis was performed with GeneSpring GX 11.5 (RMA algorithm). Pathway and network analysis was performed with the gene ontology software Ingenuity Pathways Analysis (Ingenuity® Systems, www.ingenuity.com, Redwood City, CA, USA). Samples were grouped and background intensity values were removed (cutoff at the lowest 20th percentile). A one-way ANOVA test (P< 0.05) was performed with Benjamini-Hochberg multiple testing correction. MAIN RESULTS: Significant differences were seen in endometrial gene expression, related to the type of ovulation trigger and luteal phase support. However, the endometrial gene expression after the GnRH agonist trigger and a modified luteal phase support (B) was similar to the pattern seen after the hCG trigger (A). LIMITATIONS, REASONS FOR CAUTION: The study was performed in four oocyte donors only; however, it is a strength of the study that the same donor underwent four consecutive stimulation protocols within 1 year to avoid inter-individual variations. WIDER IMPLICATIONS OF THE FINDINGS: These endometrial gene-expression findings support the clinical reports of a non-significant difference in live birth rates between the GnRH agonist trigger and the hCG trigger, when the GnRH agonist trigger is followed by a bolus of 1500 IU hCG at 35 h post trigger in addition to the standard luteal phase support. STUDY FUNDING/ COMPETING INTERESTS: This study was supported by an un-restricted research grant by MSD Belgium. TRIAL REGISTRATION NUMBER: EudraCT number 2009-009429-26, protocol number 997 (P06034).
Assuntos
Endométrio/efeitos dos fármacos , Hormônio Foliculoestimulante Humano/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/análogos & derivados , Antagonistas de Hormônios/farmacologia , Fase Luteal/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Adulto , Gonadotropina Coriônica/farmacologia , Endométrio/metabolismo , Feminino , Fertilização in vitro , Perfilação da Expressão Gênica , Hormônio Liberador de Gonadotropina/farmacologia , Humanos , Fase Luteal/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Doação de Oócitos , Recuperação de Oócitos , Indução da Ovulação , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Doadores de Tecidos , Pamoato de Triptorrelina/farmacologiaRESUMO
BACKGROUND: Chronic endometritis is associated with abnormal uterine bleeding, recurrent abortion and infertility. It is a subtle condition, and therefore is difficult to diagnose. The diagnosis is ultimately based on the presence of plasma cells in the endometrial stroma on histopathological examination. Literature on the reproducibility of the diagnosis of chronic endometritis is lacking. Therefore, the aim of the current study was to assess the interobserver agreement of two pathologists in diagnosing chronic endometritis in asymptomatic, infertile patients. METHODS: In the context of a randomized controlled trial, an endometrial biopsy was taken during a screening hysteroscopy prior to IVF. All endometrial samples were independently examined by two pathologist. The slides diagnosed with chronic endometritis were replenished with a random sample of the remaining slides up to a total of 100, then exchanged between the two pathologists and reassessed. RESULTS: Of the 678 patients who underwent hysteroscopy, 19 patients were diagnosed with at least possible chronic endometritis (2.8%). Perfect agreement between the pathologists, before and after inclusion of 13 slides with additional immunohistochemistry staining, was found in 88 and 86% of reviews, respectively. The interobserver agreement was substantial, with kappa-values of 0.55 and 0.66, respectively. CONCLUSIONS: The interobserver agreement in diagnosing chronic endometritis in asymptomatic infertile patients was found to be substantial. Although the diagnostic reliability is sufficient with the methods in the present study, the low prevalence and unknown clinical significance of endometritis warrants further study.
Assuntos
Endometrite/diagnóstico , Fertilização in vitro/métodos , Adulto , Biópsia/métodos , Doença Crônica , Endometrite/patologia , Endométrio/patologia , Feminino , Ginecologia/métodos , Humanos , Histeroscopia/métodos , Imuno-Histoquímica/métodos , Variações Dependentes do Observador , Patologia/métodos , Prevalência , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Grafting of frozen-thawed testicular tissue has been suggested as a novel fertility preservation method for patients undergoing gonadotoxic treatments. However, this technique still needs further optimization before any clinical application. So far, grafting of human testicular tissue has only been performed to the back skin of nude mice and has shown spermatogonial stem-cell survival and occasionally differentiation up to primary spermatocytes. In this study, orthotopic grafting to mouse testes was evaluated as an alternative, and the effect of freezing and the donor's age was studied. METHODS: Human testicular tissue was obtained from two prepubertal (aged 3 and 5) and two postpubertal (aged 12 and 13) boys. Both fresh and frozen-thawed testicular tissue was grafted to the testis of immuno-deficient nude mice. Four and nine months after transplantation, testes were analyzed by histology and immunohistochemistry. RESULTS: Four and nine months after transplantation, spermatogonial stem cells were observed in all tissue grafts. Germ cell survival was found to be higher in xenografts from the older boys when compared with that from younger donors. Furthermore, no differentiation was observed in the xenografts from younger patients, but the grafts of two older donors showed differentiation up to the primary spermatocyte level, with the presence of secondary spermatocytes in the oldest donor 9 months after transplantation. CONCLUSIONS: This xenografting study shows that intratesticular grafting results in high germ cell survival. In grafts derived from the older boys, meiotic activity was maintained in the xenografts for at least 9 months. Although difficult to conduct due to the scarcity of the tissue, more comparative research is needed to elucidate an optimal grafting strategy.
Assuntos
Espermatogênese , Testículo/transplante , Adolescente , Animais , Diferenciação Celular , Sobrevivência Celular , Criança , Pré-Escolar , Humanos , Masculino , Meiose , Camundongos , Camundongos Nus , Puberdade , Espermatogônias/transplante , Testículo/cirurgia , Transplante HeterólogoRESUMO
Premature progesterone rise during gonadotrophin-releasing hormone (GnRH) antagonist cycles for IVF is a frequent phenomenon and has been associated with lower pregnancy and implantation rates. This study evaluated endometrial gene expression on the day of oocyte retrieval according to the concentration of serum progesterone on the day of human chorionic gonadotrophin (HCG) administration in GnRH-antagonist/recombinant FSH IVF cycles with fresh embryo transfer. Endometrial biopsies (n=14) were analysed with Affymetrix HG U133 Plus 2.0 Arrays. Patients were divided into three groups according to their progesterone serum concentration on the day of HCG administration: ≤ 0.9 ng/ml (group A), 1-1.5 ng/ml (group B) and >1.5 ng/ml (group C). Gene expression analysis showed a small number of significantly differentially expressed probe sets between groups A and B (five up/23 down in B) and a large difference between groups B and C (607 up/212 down; P ≤ 0.05, fold change ≥ 1.4). Validation was performed with quantitative real-time PCR on selected genes. As far as is known, this is the first study to demonstrate a distinct difference in endometrial gene expression profile between patients with a progesterone serum concentration above and below the threshold of 1.5 ng/ml on the day of HCG administration.
Assuntos
Gonadotropina Coriônica/administração & dosagem , Endométrio/metabolismo , Hormônio Foliculoestimulante/farmacologia , Regulação da Expressão Gênica/fisiologia , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Ciclo Menstrual/efeitos dos fármacos , Progesterona/sangue , Feminino , Fertilização in vitro/efeitos dos fármacos , Fertilização in vitro/métodos , Humanos , Análise em Microsséries , Reação em Cadeia da Polimerase , GravidezRESUMO
OBJECTIVE: To evaluate the preoperative detection of axillary metastasis combining ultrasound (US)-guided fine needle aspiration cytology (FNAC) and liquid-based cytology (Surepath(®)) to reduce sentinel node procedures. METHODS: In total, 148 patients with clinically negative lymph nodes and no preoperative therapy were included. All patients underwent preoperative ultrasound of the axilla with FNAC if suspicious lymph nodes were found. Complete axillary lymph node dissection was performed at primary surgery when FNAC was positive. All other patients underwent a sentinel node procedure. RESULTS: US-guided FNAC of the axilla revealed metastasis in 34 (23.0%) of the 148 patients. These 34 patients were 53.1% of all patients (n = 64) with proven axillary lymph node involvement. In 66 patients (44.6%), both ultrasound and histopathology were negative. Overall sensitivity of US-guided FNAC was 50.0%, specificity 100%, positive predictive value 100% and negative predictive value 70.2%. In T1 tumours, all patients referred for sentinel node procedure were node-negative. The correlation between malignant FNAC and histopathology was 100%. US-guided liquid-based FNAC in patients with no clinically positive lymph nodes reduced the necessity for a sentinel node procedure by 23.0%. CONCLUSIONS: We advocate that US-guided fine needle aspiration (FNA) combined with liquid-based cytology of axillary lymph nodes should be included in the preoperative staging of breast cancer.
Assuntos
Axila/diagnóstico por imagem , Biópsia por Agulha Fina/métodos , Neoplasias da Mama/diagnóstico por imagem , Linfonodos/diagnóstico por imagem , Metástase Linfática/diagnóstico por imagem , Estadiamento de Neoplasias/métodos , Ultrassonografia de Intervenção/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Axila/patologia , Axila/cirurgia , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/patologia , Linfonodos/cirurgia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Biópsia de Linfonodo Sentinela/métodosRESUMO
OBJECTIVES: A prospective study was carried out to evaluate the role of intra-operative touch imprint cytology (TIC) in the assessment of sentinel lymph node (SLN) involvement for staging and treatment of early-stage, clinically node-negative breast carcinoma. METHODS: Forty-five patients with early-stage, clinically node-negative breast cancer underwent a SLN biopsy with intra-operative TIC. The SLN was bisected if its width was less than 4 mm or sliced every 2 mm if it was more than 4 mm. The imprint specimens were stained with haematoxylin and eosin (H&E). Rapid immunochemistry (IH) was performed in case of equivocal cytological result. Permanent sections were evaluated with H&E and IH staining. The results of TIC were compared to histopathological results. RESULTS: The sensitivity, specificity and overall accuracy of TIC on a node basis were 65.5%, 96.3%, 85.5%, respectively. When calculated according to the size of SLN metastasis, the sensitivity of TIC for overt metastasis was 84.6%, while it was 62.5% for micrometastasis and 37.5% for sub-micrometastasis. The mean size of nodal metastasis was 5.08 mm and 1.25 mm for true positive and false negative results, respectively (P = 0.0236). Because of intra-operative TIC, 76.5% of the patients who needed further axillary lymph node dissection (ALND) could undergo this during the same operating time. CONCLUSIONS: TIC is a rapid and reliable method for the intra-operative assessment of metastatic sentinel node involvement in patients with early-stage, clinically node-negative breast carcinoma. Despite a low sensitivity comparable to frozen section (FS) in detecting micro- and sub-micrometastases, the technique offers the advantage of full tissue preservation for subsequent histological analysis.
Assuntos
Biópsia/métodos , Neoplasias da Mama/patologia , Técnicas Citológicas/métodos , Estadiamento de Neoplasias/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/cirurgia , Feminino , Seguimentos , Humanos , Período Intraoperatório , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
Providing valid risk estimates of a genetic disease with variable age of onset is a major challenge for prevention strategies. When data are obtained from pedigrees ascertained through affected individuals, an adjustment for ascertainment bias is necessary. This article focuses on ascertainment through at least one affected and presents an estimation method based on maximum likelihood, called the Proband's phenotype exclusion likelihood or PEL for estimating age-dependent penetrance using disease status and genotypic information of family members in pedigrees unselected for family history. We studied the properties of the PEL and compared with another method, the prospective likelihood, in terms of bias and efficiency in risk estimate. For that purpose, family samples were simulated under various disease risk models and under various ascertainment patterns. We showed that, whatever the genetic model and the ascertainment scheme, the PEL provided unbiased estimates, whereas the prospective likelihood exhibited some bias in a number of situations. As an illustration, we estimated the disease risk for transthyretin amyloid neuropathy from a French sample and a Portuguese sample and for BRCA1/2 associated breast cancer from a sample ascertained on early-onset breast cancer cases.
Assuntos
Doenças Genéticas Inatas/genética , Fatores Etários , Neuropatias Amiloides/genética , Viés , Neoplasias da Mama/genética , França , Genes BRCA1 , Genes BRCA2 , Humanos , Funções Verossimilhança , Modelos Genéticos , Modelos Estatísticos , Linhagem , Fenótipo , Portugal , Pré-Albumina/genética , RiscoRESUMO
More than 3 days' luteal endometrial advancement in IVF has been related with no pregnancies. This study assessed the effect of recombinant and urinary human chorionic gonadotrophin (recHCG and uHCG) when administered for final oocyte maturation on the advancement of endometrial histology. Thirty patients were randomized to receive either 250 microg recHCG or 10,000 IU uHCG in an antagonist/recombinant FSH protocol. Endometrial biopsy was performed on the day of oocyte retrieval. All specimens were evaluated according to Noyes' criteria by one pathologist blinded to the allocation treatment groups. Single blastocyst transfer was performed. Overall, 13 patients in recHCG group and 14 patients in uHCG group underwent endometrial biopsy. The mean days of histological endometrial advancement were comparable between the two groups: 2.03 versus 2.17days, respectively. Nevertheless more patients (69%, 9/13) had less than 3 days' advanced endometrium in the recHCG arm as compared with 43% (6/14) patients in the uHCG group (OR 3.00, 95% CI 0.4-16.3). The delivery rate per patient was higher, although not significantly, in the recHCG group (38.5% versus 28.6%). Both recHCG and uHCG preparations induce advancement of endometrial maturation. Whether a subtle difference in endometrial maturation affects the reproductive outcome remains to be proven.
Assuntos
Gonadotropina Coriônica/uso terapêutico , Endométrio/efeitos dos fármacos , Adulto , Biópsia , Gonadotropina Coriônica/urina , Endométrio/patologia , Feminino , Humanos , Recuperação de Oócitos , Indução da Ovulação/métodos , Projetos Piloto , Gravidez , Resultado da Gravidez , Proteínas Recombinantes/uso terapêuticoRESUMO
A European Federation of Cytology Societies (EFCS) working party of 28 members from 14 European countries met at the European Congress of Cytology in Lisbon in September 2009, with two observers from the USA, to discuss the need for standardising thyroid FNA nomenclature in the light of the National Institute of Cancer (NCI) recommendations resulting from the State of the Science conference in Bethesda in 2007. The data were obtained through two questionnaires sent by email and a transcript of the live discussion at the congress, which is presented in full. The surveys and discussion showed that there were currently no national terminologies for reporting thyroid FNA in the different European countries except in Italy and the UK. Personal, 'local', surgical pathology and descriptive terminologies were in use. All but one of the working party members agreed that thyroid FNA reporting should be standardised. Whilst almost a third would adopt the NCI Bethesda terminology, which offers the advantages of a 'risk of cancer' correlation and is linked to clinical recommendations, more than half favoured a translation of local terminology as the first step towards a unified nomenclature, as has been done recently in the UK. There was some disagreement about the use of: a) the six-tiered as opposed to four or five-tiered systems, b) the use of an indeterminate category and c) the 'follicular neoplasm' category, which was felt by some participants not to be different from the 'suspicious of malignancy' category. The conclusions will be passed to the different national societies of cytology for discussion, who will be asked to map their local terminologies to the Bethesda classification, observe its acceptance by clinicians and audit its correlation with outcome.
Assuntos
Biópsia por Agulha Fina , Doenças da Glândula Tireoide/patologia , Glândula Tireoide/patologia , Biópsia por Agulha Fina/métodos , Biópsia por Agulha Fina/normas , Europa (Continente) , Humanos , Guias de Prática Clínica como Assunto , Terminologia como AssuntoRESUMO
BACKGROUND: The purpose of this prospective observational study was to evaluate the association between estradiol (E(2)) levels on the day of human chorionic gonadotrophin (hCG) administration and pregnancy rates in a recombinant FSH (rec-FSH) antagonist fixed protocol. METHODS: A group of 207 patients (
Assuntos
Gonadotropina Coriônica/farmacologia , Estradiol/sangue , Hormônio Foliculoestimulante/farmacologia , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Proteínas Recombinantes/farmacologia , Adulto , Transferência Embrionária , Feminino , Fertilização in vitro , Humanos , Modelos Lineares , Gravidez , Taxa de Gravidez , Estudos ProspectivosRESUMO
Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2-3 years of tamoxifen, or as an extended treatment after 5 years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerance in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded. In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients. Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.
Assuntos
Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Nitrilas/efeitos adversos , Triazóis/efeitos adversos , Idoso , Antineoplásicos/uso terapêutico , Artralgia/induzido quimicamente , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Letrozol , Mastectomia , Pessoa de Meia-Idade , Pós-Menopausa , Estudos RetrospectivosRESUMO
Most participating countries have now adopted a triple assessment approach, i.e. clinical,imaging and pathology, to breast diagnosis, with FNAC as the first-line pathological investigation in both screening and symptomatic populations, with the exception of microcalcifications. Pathologists specialized in cytopathology are best qualified to collect and interpret FNAC samples, but this is not always possible or practical. Radiologists involved in breast imaging should ensure that they have the necessary skills to carry out FNAC under all forms of image guidance. Best results are achieved by a combination of both techniques, as shown in the image-guided FNAC in the presence of the cytopathologist. The majority of European countries use similar reporting systems for breast FNAC (C1-C5), in keeping with European Guidelines for Quality Assurance in Breast Cancer Screening and Diagnosis, although some still prefer descriptive reporting only. When triple assessment is concordant, final treatment may proceed on the basis of FNAC, without a tissue biopsy. ER and PR assessment can be done safely on FNAC material. However, not all institutions may have expertise in doing this. HER-2 protein expression on direct cytological preparations is insufficiently reliable for clinical use, although its use for FISH is possible, if expertise is available. The majority of participants practise a degree of one-stop diagnosis with a cytopathologist present in the out-patient clinic. Formal recognition of the importance of the time spent outside the laboratory, both for cytopathologist and cytotechnologist, is necessary in order to ensure appropriate resourcing. The use of core biopsy (CB) has increased, although not always for evidence-based reasons. CB and FNAC are not mutually exclusive. FNAC should be used in diagnosis of benign, symptomatic lesions and CB in microcalcifications, suspicious FNAC findings and malignancies where radiology cannot guarantee stromal invasion.
Assuntos
Biópsia por Agulha Fina , Doenças Mamárias , Mama/patologia , Biópsia por Agulha Fina/normas , Biópsia por Agulha Fina/estatística & dados numéricos , Doenças Mamárias/diagnóstico , Doenças Mamárias/patologia , Doenças Mamárias/terapia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Feminino , Humanos , Receptor ErbB-2/metabolismoRESUMO
We have previously shown that patients with renal fibromuscular dysplasia (FMD) have asymptomatic carotid lesions and that familial forms may occur. The objective of this study was to test whether carotid lesions could be detected in relatives of familial cases. High-resolution echotracking of the carotid artery was performed in 47 relatives of 13 cases from six families. This non-invasive investigation led to a semiquantitative arterial score that was compared with that obtained for 47 controls matched for age and sex and that for 125 sporadic cases. Familial resemblance was tested by using a generalized estimating equation approach taking into account the clustering of scores in families. As expected, FMD cases had a significantly higher score than controls (4.02 vs 2.52, P<10(-5)). Familial cases were not significantly different from sporadic cases. Of interest, the 47 apparently healthy relatives of familial cases had also a high carotid score (4.17), very significantly higher than that of controls (2.52, P<10(-5)) even though lower than the corresponding index FMD cases (4.81, P=0.01). Segregation analysis showed that 52% of the descendants of subjects with a score >4 had a score >4, a proportion consistent with autosomal-dominant transmission of the trait. Altogether these results strengthen the hypothesis of renal FMD being a systemic arterial disease and argue for a familial resemblance that may be due to a major genetic effect. The carotid score obtained by high-resolution echotracking may provide a non-invasive surrogate marker for renal FMD of potential value for use in linkage strategies on large pedigrees.
Assuntos
Doenças das Artérias Carótidas/genética , Artéria Carótida Primitiva/patologia , Displasia Fibromuscular/genética , Obstrução da Artéria Renal/genética , Adulto , Idoso , Análise de Variância , Doenças das Artérias Carótidas/complicações , Estudos de Casos e Controles , Análise por Conglomerados , Feminino , Displasia Fibromuscular/complicações , França , Predisposição Genética para Doença , Humanos , Hipertensão/etiologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Curva ROC , Análise de Regressão , Obstrução da Artéria Renal/complicações , Projetos de Pesquisa , Análise de Sobrevida , Túnica Íntima/patologia , Túnica Média/patologiaRESUMO
The specific interaction of blastocyst-derived human chorionic gonadotropin (hCG) and endometrial LH/hCG-R constitutes a fundamental component of the molecular dialogue at the materno-fetal interface. From our observations and studies from other groups, hCG was indeed shown to play a significant role in implantation and tolerance of the embryo, decidual differentiation and remodeling, as well as in placentation. The profile pattern of LH/hCG-R expression by endometrial epithelium correlates with the theoretical timing of the implantation window. Studies are currently being conducted in assisted medical procreation and in an animal model of implantation to establish the index of LH/hCG-R expression as a new biomarker of uterine receptivity for embryo implantation.
Assuntos
Blastocisto/fisiologia , Gonadotropina Coriônica/fisiologia , Implantação do Embrião/fisiologia , Endométrio/fisiologia , Gravidez/fisiologia , Receptores do LH/fisiologia , Feminino , Humanos , Hormônio Luteinizante/fisiologiaRESUMO
We present a case of lower limb sensory disturbances and weakness in a patient originating from Mali. MRI showed a diffuse myelopathy of the cervical and thoracic spinal cord. Serological evaluation of blood and cerebrospinal fluid pointed towards schistosomiasis as the cause. Histological confirmation was made on bladder-biopsy. Treatment with praziquantel and steroids brought marked clinical improvement. This case illustrates the need to keep in mind more exotic causes of myelopathy in those patients coming from endemic regions.