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PURPOSE: The purpose of this study is to investigate whether retained hardware after surgical treatment for a pelvic fracture prior to pregnancy affects the choice of delivery method. The study aims to provide insights into the rates of vaginal delivery and caesarean sections, understanding whether the mode of delivery was influenced by patient preference or the recommendations of obstetricians or surgeons, and examining the rate of complications during delivery and postpartum. METHODS: All women of childbearing age who underwent surgical fixation for a pelvic ring fracture between 1994 and 2021 were identified. A questionnaire was sent about their possible pregnancies and deliveries. Of the included patients, surgical data were collected and the fracture patterns were retrospectively classified. Follow-up was a minimum of 36 months. RESULTS: A total of 168 women with a pelvic fracture were identified, of whom 13 had a pregnancy after surgical stabilization. Eleven women had combined anterior and posterior fracture patterns and two had isolated sacral fractures. Four women underwent combined anterior and posterior fixation, the others either anterior or posterior fixation. Seven women had a total of 11 vaginal deliveries, and 6 women had 6 caesarean sections. The decision for vaginal delivery was often the wish of the mother (n = 4, 57%) while the decision to opt for caesarean section was made by the surgeon or obstetrician (n = 5, 83%). One woman in the vaginal delivery group suffered a postpartum complication possibly related to her retained pelvic hardware. CONCLUSION: Women with retained hardware after pelvic ring fixation can have successful vaginal deliveries. Complications during labor or postpartum are rare. The rate of primary caesarean sections is high (46%) and is probably influenced by physician bias. Future research should focus on tools that can predict labor outcomes in this specific population, and larger multicenter studies are needed. LEVEL OF EVIDENCE: Level III.
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Background: Although medical courses are frequently evaluated via surveys with Likert scales ranging from "strongly agree" to "strongly disagree," low response rates limit their utility. In undergraduate medical education, a new method with students predicting what their peers would say, required fewer respondents to obtain similar results. However, this prediction-based method lacks validation for continuing medical education (CME), which typically targets a more heterogeneous group than medical students. Methods: In this study, 597 participants of a large CME course were randomly assigned to either express personal opinions on a five-point Likert scale (opinion-based method; n = 300) or to predict the percentage of their peers choosing each Likert scale option (prediction-based method; n = 297). For each question, we calculated the minimum numbers of respondents needed for stable average results using an iterative algorithm. We compared mean scores and the distribution of scores between both methods. Results: The overall response rate was 47%. The prediction-based method required fewer respondents than the opinion-based method for similar average responses. Mean response scores were similar in both groups for most questions, but prediction-based outcomes resulted in fewer extreme responses (strongly agree/disagree). Conclusions: We validated the prediction-based method in evaluating CME. We also provide practical considerations for applying this method.
Contexte: Bien que les cours de médecine soient fréquemment évalués au moyen d'enquêtes avec des échelles de Likert allant de « totalement d'accord ¼ à « totalement en désaccord ¼, les faibles taux de réponse en limitent l'utilité. Dans l'enseignement médical prédoctoral, une nouvelle méthode dans laquelle les étudiants prédisent ce que leurs pairs diraient, nécessite moins de répondants pour obtenir des résultats similaires. Cependant, cette méthode fondée sur la prédiction n'est pas validée pour la formation médicale continue (FMC), qui cible généralement un groupe plus hétérogène que les étudiants en médecine. Méthodes: Dans cette étude, 597 participants à un grand cours de FMC ont été choisis au hasard pour exprimer leur opinion personnelle sur une échelle de Likert en cinq points (méthode fondée sur l'opinion; n = 300) ou à prédire le pourcentage de leurs pairs choisissant chaque option de l'échelle de Likert (méthode fondée sur la prédiction; n = 297). Pour chaque question, nous avons calculé le nombre minimum de répondants nécessaire pour obtenir des résultats moyens stables à l'aide d'un algorithme itératif. Nous avons comparé les scores moyens et la distribution des scores entre les deux méthodes. Résultats: Le taux de réponse global était de 47 %. La méthode fondée sur la prédiction a nécessité moins de répondants que celle fondée sur l'opinion pour des réponses moyennes similaires. Les scores moyens des réponses étaient similaires dans les deux groupes pour la plupart des questions, mais les résultats fondés sur la prédiction ont donné lieu à moins de réponses extrêmes (totalement d'accord/totalement en désaccord). Conclusions: Nous avons validé la méthode fondée sur la prédiction dans l'évaluation de la FMC. Nous présentons également des considérations pratiques pour la mise en Åuvre de cette méthode.
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Educação Médica Continuada , Grupo Associado , Humanos , Educação Médica Continuada/métodos , Avaliação Educacional/métodos , Masculino , Feminino , Inquéritos e Questionários , Estudantes de Medicina/psicologia , Estudantes de Medicina/estatística & dados numéricos , AdultoRESUMO
Despite the fact that the role of endoglin on endothelial cells has been extensively described, its expression and biological role on (epithelial) cancer cells is still debatable. Especially its function on squamous cell carcinoma (SCC) cells is largely unknown. Therefore, we investigated SCC endoglin expression and function in three types of SCCs; head and neck (HNSCC), esophageal (ESCC) and vulvar (VSCC) cancers. Endoglin expression was evaluated in tumor specimens and 14 patient-derived cell lines. Next to being expressed on angiogenic endothelial cells, endoglin is selectively expressed by individual SCC cells in tumor nests. Patient derived HNSCC, ESCC and VSCC cell lines express varying levels of endoglin with high interpatient variation. To assess the function of endoglin in signaling of TGF-ß ligands, endoglin was overexpressed or knocked out or the signaling was blocked using TRC105, an endoglin neutralizing antibody. The endoglin ligand BMP-9 induced strong phosphorylation of SMAD1 independent of expression of the type-I receptor ALK1. Interestingly, we observed that endoglin overexpression leads to strongly increased soluble endoglin levels, which in turn decreases BMP-9 signaling. On the functional level, endoglin, both in a ligand dependent and independent manner, did not influence proliferation or migration of the SCC cells. In conclusion, these data show endoglin expression on individual cells in the tumor nests in SCCs and a role for (soluble) endoglin in paracrine signaling, without directly affecting proliferation or migration in an autocrine manner.
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BACKGROUND: Although the risk for transplacental transmission of SARS-CoV-2 is rare, placental infections with adverse functional consequences have been reported. This study aims to analyse histological placental findings in pregnancies complicated by SARS-CoV-2 infection and investigate its correlation with clinical symptoms and perinatal outcomes. We want to determine which pregnancies are at-risk to prevent adverse pregnancy outcomes related to COVID-19 in the future. METHODS: A prospective, longitudinal, multicentre, cohort study. All pregnant women presenting between April 2020 and March 2021 with a nasopharyngeal RT-PCR-confirmed SARS-CoV-2 infection were included. Around delivery, maternal, foetal and placental PCR samples were collected. Placental pathology was correlated with clinical maternal characteristics of COVID-19. RESULTS: Thirty-six patients were included, 33 singleton pregnancies (n = 33, 92%) and three twin pregnancies (n = 3, 8%). Twenty-four (62%) placentas showed at least one abnormality. Four placentas (4/39, 10%) showed placental staining positive for the presence of SARS-CoV-2 accompanied by a unique combination of diffuse, severe inflammatory placental changes with massive perivillous fibrin depositions, necrosis of syncytiotrophoblast, diffuse chronic intervillositis, and a specific, unprecedented CD20+ B-cell infiltration. This SARS-CoV-2 placental signature seems to correlate with foetal distress (75% vs. 15.6%, p = 0.007) but not with the severity of maternal COVID-19 disease. CONCLUSION: We describe a unique placental signature in pregnant patients with COVID-19, which has not been reported in a historical cohort. We show that the foetal environment can be seriously compromised by disruption of placental function due to local, devastating SARS-CoV-2 infection. Maternal clinical symptoms did not predict the severity of the SARS-CoV-2-related placental signature, resulting in a lack of adequate identification of maternal criteria for pregnancies at risk. Close foetal monitoring and pregnancy termination in case of foetal distress can prevent adverse pregnancy outcomes due to COVID-19 related placental disease.
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COVID-19/patologia , Doenças Placentárias/patologia , Placenta/patologia , Complicações Infecciosas na Gravidez/patologia , Adulto , COVID-19/fisiopatologia , COVID-19/virologia , Feminino , Sofrimento Fetal/fisiopatologia , Humanos , Estudos Longitudinais , Placenta/fisiopatologia , Placenta/virologia , Doenças Placentárias/fisiopatologia , Doenças Placentárias/virologia , Gravidez , Complicações Infecciosas na Gravidez/fisiopatologia , Complicações Infecciosas na Gravidez/virologia , Resultado da Gravidez , Estudos Prospectivos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Trofoblastos/patologiaRESUMO
OBJECTIVE: To investigate the prevalence of somatic mutations in Indonesian cervical carcinoma patients in the context of histology and human papillomavirus (HPV) type. METHODS: In total 174 somatic hot-spot mutations in 13 genes were analyzed by mass spectrometry in 137 Indonesian cervical carcinomas. RESULTS: In 66/137 tumors (48%) 95 mutations were identified. PIK3CA was most frequently mutated (24%), followed by FBXW7 (7%), CTNNB1 (6%), and PTEN (6%). In squamous cell carcinomas more often multiple mutations per sample (p=0.040), and more PIK3CA (p=0.039) and CTNNB1 (p=0.038) mutations were detected compared to adenocarcinomas. PIK3CA mutations were associated with HPV 16 positivity, CDKN2A mutations with HPV 52 positivity, and, interestingly, PTEN mutations with HPV negativity. Balinese tumor samples more often carried multiple mutations (p=0.019), and more CTNNB1, CDKN2A, and NRAS mutations compared to Javanese tumor samples. CONCLUSIONS: Potentially targetable somatic mutations occurred in 48% of Indonesian cervical carcinomas. The landscape of mutations is predominated by mutations concerning the PI3K pathway, and we prompt for more research on developing therapies targeting this pathway, explicitly for the more advanced stage cervical carcinoma patients.
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Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/genética , Adulto , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Humanos , Indonésia , Espectrometria de Massas , Pessoa de Meia-Idade , Análise Multivariada , PTEN Fosfo-Hidrolase/genética , Transdução de Sinais , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , beta Catenina/genéticaRESUMO
BACKGROUND: Vulvar cancer treatment is mostly curative, but also has high morbidity rates. In a search for markers that can identify patients at risk of metastases, we investigated the prognostic value of L1-cell adhesion molecule (L1CAM) in large series of vulvar squamous cell carcinomas (VSCCs). L1CAM promotes cell motility and is an emerging prognostic factor for metastasis in many cancer subtypes. RESULTS: L1CAM expression was observed at the invasive front or in spray-patterned parts of 17% of the tumours. L1CAM-positive tumours expressed vimentin more often, but L1CAM expression was not associated with TP53 or CTNNB1 mutations. Five-year survival was worse for patients with L1CAM expression (overall survival 46.1% vs 63.6%, P=.014, disease specific survival 63.8% vs 80.0%, P=.018). Multivariate analysis indicates L1CAM expression as an independent prognostic marker (HR 2.9, 95% CI 1.10-7.68). An in vitro spheroid invasion assay showed decreased invasion of L1CAM-expressing VSCC spindle cells after treatment with L1CAM-neutralising antibodies. METHODS: Paraffin-embedded tumour tissue from two cohorts (N=103 and 245) of primary VSCCs were stained for L1CAM, vimentin and E-cadherin. Patients of the first cohort were tested for human papilloma virus infection and sequenced for TP53 and CTNNB1 (ß-catenin) mutations. The expression of L1CAM was correlated to clinical characteristics and patient survival. CONCLUSION: This is the first study to show high L1CAM-expression at the infiltrating margin of VSCC's. L1CAM-expressing VSCCs had a significantly worse prognosis compared to L1CAM-negative tumours. The highest expression was observed in spindle-shaped cells, where it might be correlated to their invasive capacity.
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Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Recidiva Local de Neoplasia/patologia , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neoplasias Vulvares/patologia , Idoso , Carcinoma de Células Escamosas/metabolismo , Feminino , Humanos , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Taxa de Sobrevida , Neoplasias Vulvares/metabolismoRESUMO
INTRODUCTION: Squamous cell carcinoma (SCC), adenocarcinoma (AC), and adenosquamous carcinoma (ASC) are the most common histological subtypes of cervical cancer. Differences in the somatic mutation profiles of these subtypes have been suggested. We investigated the prevalence of somatic hot-spot mutations in three well-defined cohorts of SCC, AC, and ASC and determined the additional value of mutation profiling in predicting disease outcome relative to well-established prognostic parameters. MATERIALS AND METHODS: Clinicopathological data were collected for 301 cervical tumors classified as SCC (n=166), AC (n=55), or ASC (n=80). Mass spectrometry was used to analyze 171 somatic hot-spot mutations in 13 relevant genes. RESULTS: In 103 (34%) tumors, 123 mutations were detected (36% in SCC, 38% in AC, and 28% in ASC), mostly in PIK3CA (20%) and KRAS (7%). PIK3CA mutations occurred more frequently in SCC than AC (25% vs. 11%, P=0.025), whereas KRAS mutations occurred more frequently in AC than SCC (24% vs. 3%, P<0.001) and ASC (24% vs. 3%, P<0.001). A positive mutation status correlated with worse disease-free survival (HR 1.57, P=0.043). In multivariate analysis, tumor diameter, parametrial infiltration, and lymph node metastasis, but not the presence of a somatic mutation, were independent predictors of survival. CONCLUSION: Potentially targetable somatic mutations occurred in 34% of cervical tumors with different distributions among histological subtypes. Precise classification of cervical carcinomas in combination with mutation profiling is valuable for predicting disease outcome and may guide the development and selection of tumor-specific treatment approaches.
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Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Mutação , Neoplasias do Colo do Útero/genética , Adenocarcinoma/classificação , Adenocarcinoma/patologia , Adulto , Proteínas Adaptadoras de Sinalização CARD , Carcinoma de Células Escamosas/classificação , Carcinoma de Células Escamosas/patologia , Classe I de Fosfatidilinositol 3-Quinases , Proteínas do Citoesqueleto/genética , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias do Colo do Útero/classificação , Neoplasias do Colo do Útero/patologiaRESUMO
Vulvar cancer is a relatively rare gynecologic malignancy with an annual incidence in developed countries of approximately 2 per 100,000 women. Vulvar squamous cell carcinoma (VSCC) has two etiological pathways: a high risk human papillomavirus (HPV)-dependent route, which has usual vulvar intraepithelial neoplasia (uVIN) as a precursor lesion, and an HPV-independent route, which is associated with differentiated VIN (dVIN), lichen sclerosus, and genetic alterations, such as TP53 mutations. Research on the molecular etiology of vulvar cancer has increased in the past years, not only regarding genetic alterations, but also epigenetic changes. In genetic alterations, a mutation irreversibly changes the nucleotide sequence of the DNA, or the number of copies of chromosomes per cell is altered. In epigenetics, the nucleotide sequence remains the same but genes can be 'switched' on or off by, for example, DNA methylation or histone modification. We searched the current literature on genetic and epigenetic alterations in VSCC and its precursor lesions. Many studies have reported a higher incidence of somatic mutations in HPV-negative tumors compared to HPV-positive tumors, with TP53 mutations being the most frequent. Allelic imbalances or loss of heterozygosity are more frequently found in higher stages of dysplasia and in invasive carcinomas, but it is not exclusive to HPV-negative tumors. A limited number of studies are available on epigenetic changes in vulvar lesions, with hypermethylation of CDKN2A being the most frequently investigated change. For most genes, hypermethylation occurs more frequently in vulvar squamous cell carcinomas than in precursor lesions. As most studies have focused on HPV infection and TP53 mutations, we suggest that more research should be performed using whole genome or next generation sequencing to determine the true landscape of genetic and epigenetic alterations in vulvar squamous cell carcinoma.
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Carcinoma de Células Escamosas/genética , Neoplasias Vulvares/genética , Epigenômica , Feminino , Humanos , Lesões Pré-Cancerosas/genéticaRESUMO
BACKGROUND: Two etiologic pathways of vulvar cancer are known, a human papillomavirus (HPV)- and a TP53-associated route, respectively, but other genetic changes may also play a role. Studies on somatic mutations in vulvar cancer other than TP53 are limited in number and size. In this study, we investigated the prevalence of genetic mutations in 107 vulvar squamous cell carcinomas (VSCCs). METHODS: A total of 107 paraffin-embedded tissue samples of primarily surgically treated VSCCs were tested for HPV infection and screened for mutations in 14 genes (BRAF, CDKN2A(p16), CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53) using Sanger sequencing and mass spectrometry. RESULTS: Mutations were detected in 7 genes. Of 107 VSCCs, 66 tumors (62%) contained at least one mutation (TP53=58, CDKN2A(p16)=14, HRAS=10, PIK3CA=7, PPP2R1A=3, KRAS=1, PTEN=1). Mutations occurred most frequently in HPV-negative samples. Five-year survival was significantly worse for patients with a mutation (47% vs 59%, P=.035), with a large effect from patients carrying HRAS-mutations. CONCLUSION: Somatic mutations were detected in 62% of VSCCs. As expected, HPV infection and TP53-mutations play a key role in the development of VSCC, but CDKN2A(p16), HRAS, and PIK3CA-mutations were also frequently seen in HPV-negative patients. Patients with somatic mutations, especially HRAS-mutations, have a significantly worse prognosis than patients lacking these changes, which could be of importance for the development of targeted therapy.
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Carcinoma de Células Escamosas/genética , Genes p16 , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Vulvares/genética , Idoso , Carcinoma de Células Escamosas/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina , Feminino , Humanos , Proteínas de Neoplasias , Taxa de Sobrevida , Neoplasias Vulvares/mortalidadeRESUMO
Somatic mutations play a major role in tumour initiation and progression. The mutation status of a tumour may predict prognosis and guide targeted therapies. The majority of techniques to study oncogenic mutations require high quality and quantity DNA or are analytically challenging. Mass-spectrometry based mutation analysis however is a relatively simple and high-throughput method suitable for formalin-fixed, paraffin-embedded (FFPE) tumour material. Targeted gene panels using this technique have been developed for several types of cancer. These current cancer hotspot panels are not focussed on the genes that are most relevant in gynaecological cancers. In this study, we report the design and validation of a novel, mass-spectrometry based panel specifically for gynaecological malignancies and present the frequencies of detected mutations. Using frequency data from the online Catalogue of Somatic Mutations in Cancer, we selected 171 somatic hotspot mutations in the 13 most important genes for gynaecological cancers, being BRAF, CDKN2A, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A and PTEN. A total of 546 tumours (205 cervical, 227 endometrial, 89 ovarian, and 25 vulvar carcinomas) were used to test and validate our panel, and to study the prevalence and spectrum of somatic mutations in these types of cancer. The results were validated by testing duplicate samples and by allele-specific qPCR. The panel presented here using mass-spectrometry shows to be reproducible and high-throughput, and is usefull in FFPE material of low quality and quantity. It provides new possibilities for studying large numbers of gynaecological tumour samples in daily practice, and could be useful in guided therapy selection.