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Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
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Neoplasias da Mama/dietoterapia , Neoplasias da Mama/tratamento farmacológico , Dietoterapia/métodos , Jejum/fisiologia , Fulvestranto/uso terapêutico , Animais , Fatores Biológicos/sangue , Neoplasias da Mama/patologia , Dieta Saudável/métodos , Modelos Animais de Doenças , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Fulvestranto/administração & dosagem , Humanos , Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Leptina/sangue , Células MCF-7 , Camundongos Endogâmicos NOD , Camundongos SCID , PTEN Fosfo-Hidrolase/metabolismo , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Receptores de Estrogênio , Receptores de Progesterona , Tamoxifeno/efeitos adversos , Tamoxifeno/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent. METHODS: Within the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models. RESULTS: Eighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as "very high priority", that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient's tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors. CONCLUSIONS: PREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.
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Variações do Número de Cópias de DNA , Neuroblastoma , Lactente , Humanos , Animais , Camundongos , Recidiva Local de Neoplasia , Neuroblastoma/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Modelos Animais de Doenças , Citometria de FluxoRESUMO
Introduction: The Meet-URO 18 study is a multicentric study of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line and beyond, categorized as responders (progression-free survival ≥ 12 months) and non-responders (progression-free survival < 3 months). Areas covered: The current study includes extensive immunohistochemical analysis of T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression on tumor cells, and PD-L1 expression, on an increased sample size including 161 tumor samples (113 patients) compared with preliminary presented data. Responders' tumor tissue (n = 90; 55.9%) was associated with lower CD4 expression (p = 0.014), higher CD56 expression (p = 0.046) and higher CD8/CD4 ratio (p = 0.030). Expert opinion/commentary: The present work suggests the regulatory role of a subpopulation of T cells on antitumor response and identifies CD56 as a putative biomarker of immunotherapy efficacy.
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Introduction: The Meet-URO 18 study is a multicentric study of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line and beyond, categorized as responders (progression-free survival ≥ 12 months) and non-responders (progression-free survival < 3 months). Areas covered: The current study includes extensive immunohistochemical analysis of T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression on tumor cells, and PD-L1 expression, on an increased sample size including 161 tumor samples (113 patients) compared with preliminary presented data. Responders' tumor tissue (n = 90; 55.9%) was associated with lower CD4 expression (p = 0.014), higher CD56 expression (p = 0.046) and higher CD8/CD4 ratio (p = 0.030). Expert opinion/commentary: The present work suggests the regulatory role of a subpopulation of T cells on antitumor response and identifies CD56 as a putative biomarker of immunotherapy efficacy.
[Box: see text].
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BACKGROUND: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. METHODS: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). RESULTS: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. CONCLUSIONS: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.
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Neoplasias da Mama , Neoplasias Ovarianas , Humanos , Feminino , Virulência , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ovarianas/genética , Predisposição Genética para DoençaRESUMO
Microcystic/reticular (MRV) schwannoma has been described since 2008, but remains a rarely encountered entity. MRV has a predilection for visceral locations and has variable histologic appareances. Given its rarity and anatomic variability, this entity could raise differential diagnostic issues with other tumours and malignancies.We describe the case of a 69-year-old male followed at IRCCS Ospedale Policlinico San Martino of Genoa for his previous history of non-Hodgkin lymphoma. A para-aortic mass was discovered during follow-up, which -due to its stability, also after chemotherapy- had been hypothesized to be a non-lymphomatous lesion; given the dimensions and the site, the mass was removed. Histological evaluation showed a nodule limited by a slight fibrous capsule and characterized by a proliferation of medium-sized fusiform cells, with elongated nuclei and scarce eosinophilic cytoplasm. Given the lack of malignant signs and the strong expression of protein S-100, a diagnosis of mesenchymal neoplasia with expression of neural markers compatible with reticular schwannoma was made. The neoplasm has not recurred since its removal.The case we present is, at our best knowledge, the first described in the retroperitoneum, a site where the exclusion of other mesenchymal malignancies is mandatory. The rarity and variability of presentations could create problems of differential diagnosis both with mucinous-producing carcinomas or with other soft tissue tumours, with myxoid or reticular structure. The description of this case could help raise information on this rare neoplasm and help distinguish it from other malignancies, especially in unusual sites.
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Neurilemoma , Neoplasias de Tecidos Moles , Idoso , Diagnóstico Diferencial , Humanos , Masculino , Recidiva Local de Neoplasia/diagnóstico , Neurilemoma/diagnóstico , Neurilemoma/metabolismo , Neurilemoma/cirurgia , Proteínas S100 , Neoplasias de Tecidos Moles/diagnósticoRESUMO
INTRODUCTION: Preoperative assessment of deep endometriotic (DE) nodules is necessary to inform patients about the possible treatments and provide informed consent in case of surgery. This study aims to investigate the diagnostic performance of rectal water-contrast transvaginal ultrasonography (RWC-TVS) and sonovaginography (SVG) in women with suspicion of posterior DE. MATERIAL AND METHODS: This prospective comparative study (NCT04296760) enrolled women with clinical suspicion of DE at our institution (Piazza della Vittoria 14 SRL, Genoa, Italy). Exclusion criteria were previous diagnosis of DE by imaging techniques or laparoscopy. All patients underwent RWC-TVS and SVG, independently performed by two gynecological sonologists blinded to the other technique's results. Patients underwent laparoscopic surgery within the following three months; imaging findings were compared with surgical and histological results. RESULTS: In 208 of 281 (74.0%) patients included, posterior DE was surgically confirmed in rectosigmoid (n = 88), vagina (n = 21), rectovaginal septum (n = 34) and uterosacral ligaments (n = 156). RWC-TVS and SVG demonstrated similar sensitivity (SE; 93.8% vs 89.4%; p = 0.210) and specificity (SP; 86.3% vs 79.4%; p = 0.481) in diagnosing posterior DE. Specifically, both examinations had similar accuracy in detecting nodules of uterosacral ligaments (p = 0.779), vagina (p = 0.688) and rectovaginal septum (p = 0.824). RWC-TVS had higher SE (95.2% vs 82.0%; p = 0.003) and similar SP (99.5% vs 98.5%; p = 0.500) in diagnosing rectosigmoid endometriosis and estimated better infiltration of intestinal submucosa (p = 0.039), and distance between these nodules and anal verge (p < 0.001); only RWC-TVS allowed the estimation of bowel lumen stenosis. A similar proportion of discomfort was experienced during both examinations (p = 0.191), although a statistically higher mean visual analog score was reported during RWC-TVS (p < 0.001). CONCLUSIONS: Although RWC-TVS and SVG have similar accuracy in the diagnosis of DE, RWC-TVS performed better in assessment of the characteristics of rectosigmoid endometriosis.
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Endometriose/diagnóstico por imagem , Doenças Retais/diagnóstico por imagem , Adulto , Meios de Contraste , Feminino , Humanos , Estudos Prospectivos , Sensibilidade e Especificidade , Ultrassonografia , VaginaRESUMO
OBJECTIVES: Rectosigmoid involvement by endometriosis causes intestinal symptoms such as constipation, diarrhea, and dyschezia. A precise diagnosis about the presence, location, and extent of bowel implants is required to plan the most appropriate treatment. The aim of the study was to compare the accuracy of magnetic resonance with distension of the rectosigmoid (MR-e) with computed colonography (CTC) for diagnosing rectosigmoid endometriosis. METHODS: This study was based on the retrospective analysis of a prospectively collected database of patients with suspicion of rectosigmoid endometriosis who underwent both MR-e and CTC, and subsequently were treated by laparoscopy. The findings of imaging techniques were compared with surgical and histological results. RESULTS: Of 90 women included in the study, 44 (48.9%) had rectosigmoid nodules and underwent bowel surgery. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the diagnosis of rectosigmoid endometriosis were 88.6%, 93.5%, 92.9%, 89.6%, and 91.1% for CTC, and 93.2%, 97.9%, 97.6%, 93.8%, and 95.6% for MR-e. There was no significant difference in the accuracy of both radiologic examinations for diagnosing rectosigmoid endometriosis (P = 0.344). However, MR-e was more accurate than CTC in estimating the largest diameter of the main rectosigmoid nodule (P < 0.001). The pain perceived by the patients was significantly lower during MR-e than during CTC (P < 0.001). CONCLUSIONS: MR-e and CTC have similar diagnostic performance for the diagnosis of rectosigmoid involvement of endometriosis. However, MR-e is more accurate in the estimation of the largest diameter of main rectosigmoid nodule and more tolerated than CTC.
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Colo Sigmoide/diagnóstico por imagem , Colonografia Tomográfica Computadorizada/métodos , Endometriose/diagnóstico por imagem , Enema/métodos , Reto/diagnóstico por imagem , Adulto , Colo Sigmoide/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Estudos Prospectivos , Reto/patologia , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
This study aimed to investigate the efficacy of the etonogestrel (ENG)-releasing implant in treating patients with rectovaginal endometriosis. The study was based on the retrospective analysis of a prospectively collected database, including symptomatic women who had ultrasonographic diagnosis of rectovaginal endometriosis. Patients were follow-up at 6, 12 and 24 months from the insertion of the ENG-releasing implant. The intensity of pain symptoms was evaluated using a visual analog scale. The volume of the nodules was estimated by virtual organ computer-aided analysis. The Endometriosis Health Profile (EHP-30) was used to evaluate quality of life. Overall, 43 women were included in the study. The 2-year continuation rate for the ENG-releasing implant was 93.0%. The treatment quickly improved the intensity of non-menstrual pelvic pain, deep dyspareunia, dysmenorrhea, and dyschezia. At 6-month follow-up, there were improvements in all domains of the EHP-30 compared with baseline. Further improvements in the EHP-30 results were observed only in pain sub score at 12-month follow-up and in emotional well-being sub score at 24-month follow-up. At 6-month follow-up the volume of the rectovaginal nodules was significantly lower compared with baseline; a further decrease was observed at 12- and 24-month follow-up. The treatment was well tolerated.
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Desogestrel/administração & dosagem , Endometriose/tratamento farmacológico , Doenças Retais/tratamento farmacológico , Doenças Vaginais/tratamento farmacológico , Adulto , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/efeitos adversos , Contraceptivos Hormonais/administração & dosagem , Contraceptivos Hormonais/efeitos adversos , Desogestrel/efeitos adversos , Implantes de Medicamento , Dismenorreia/tratamento farmacológico , Dispareunia/tratamento farmacológico , Feminino , Seguimentos , Humanos , Itália , Medição da Dor , Dor Pélvica/tratamento farmacológico , Qualidade de Vida , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: To report clinical and radiographic outcomes, rate of complications and influence on spinal alignment on long-term follow-up (FU) of patients who underwent lumbar total disc arthroplasty (TDR), bringing some evidence to determine the profile of the most well-suited patients for TDR. METHODS: A retrospective review of patients underwent TDR for low back pain from degenerative disc disease (DDD) resistant to conservative treatment was performed. Demographic features, surgical data, clinical and radiographic outcomes, complications and spinopelvic parameters were evaluated. RESULTS: Thirty patients (32 TDR) were included with a mean FU of 164 ± 36.5 months. The clinical outcomes measured by visual analogue scale and Oswestry Disability Index showed a significant improvement between preoperative and 1-year FU (p < 0.01). No significant temporal variance has been identified between 1-year and long-term follow-up (p > 0.05). The surgical revision rate was 10%. The overall rate of complications was 20%. At final follow-up, the mobility of the prosthesis was preserved in 68.75% of the cases, and 73.3% of the patients were globally well aligned. CONCLUSION: The optimal surgical indication is crucial to achieve excellent clinical and radiological outcomes. According to the literature and to our experience, we underline the importance of a coronal deformity < 15° Cobb angle and a Roussouly type 1 or 2 as the profile of the most well-suited patient for TDR. Our long-term results confirm the existing evidence about efficacy and safety of TDR as a reliable option, in optimal surgery indication, to treat DDD. These slides can be retrieved under Electronic Supplementary Material.
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Degeneração do Disco Intervertebral , Disco Intervertebral , Dor Lombar , Vértebras Lombares , Substituição Total de Disco , Adolescente , Adulto , Feminino , Seguimentos , Humanos , Disco Intervertebral/cirurgia , Degeneração do Disco Intervertebral/complicações , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/cirurgia , Dor Lombar/diagnóstico , Dor Lombar/etiologia , Dor Lombar/cirurgia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Escala Visual Analógica , Adulto JovemRESUMO
INTRODUCTION: Nowadays, the resection of submucosal myomas is usually performed by hysteroscopy. No previous study has investigated the use of preoperative hormonal therapy before outpatient hysteroscopic myomectomy. OBJECTIVE: To compare the usefulness of 3-month preoperative treatment with ulipristal acetate (UPA) before outpatient hysteroscopic myomectomy in patients with FIGO (International Federation of Gynecology and Obstetrics) type 0-1 myomas. STUDY DESIGN: This prospective patient preference study included women requiring hysteroscopic resection of single FIGO type 0-1 myoma with the largest diameter <2 cm. Patients underwent either preoperative treatment with UPA (5 mg/day) for 3 months or direct surgery. Outpatient myomectomy was performed using the bipolar electrosurgical Versapoint system (Ethicon Gynecare, USA). The primary objective of the study was to compare the rate of complete resections in the 2 study groups. The secondary objective of the study was to compare the operative time and the volume of fluid infused/absorbed. The tertiary objective of the study was to assess the surgical appearance of the myomas in patients treated with UPA. RESULTS: The study included 38 women treated with UPA and 45 women who underwent direct surgery. UPA treatment significantly decreased the volume of uterine myomas (p < 0.001). The percentage of complete resection was higher in patients treated with UPA (89.5%) than in those who underwent direct surgery (68.9%; p = 0.046). Preoperative UPA treatment decreased the operative time (p < 0.001) and the volume of fluid infused (p = 0.016), but it did not significantly affect the volume of fluid absorbed (p = 0.874). The texture of the myoma was not significantly affected by UPA treatment (p = 0.142). CONCLUSIONS: Three-month UPA treatment improves the chance of single-step complete outpatient hysteroscopic resection of single FIGO type 0-1 myoma. Future randomized studies with a larger sample size should confirm these preliminary findings.
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Contraceptivos Hormonais/administração & dosagem , Histeroscopia/métodos , Leiomioma/terapia , Norpregnadienos/administração & dosagem , Cuidados Pré-Operatórios/métodos , Miomectomia Uterina/métodos , Neoplasias Uterinas/terapia , Adulto , Procedimentos Cirúrgicos Ambulatórios/métodos , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Duração da Cirurgia , Preferência do Paciente , Gravidez , Cuidados Pré-Operatórios/psicologia , Estudos Prospectivos , Resultado do TratamentoRESUMO
Currently, limited data on maternal and neonatal outcomes of pregnant women with infection and pneumonia related to SARS coronavirus 2 (SARS-CoV-2) are available. Our report aims to describe a case of placental swabs positive for the molecular research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 RNA in an asymptomatic woman with positive rhino-pharyngeal swab for SARS-CoV-2 who underwent an urgent cesarean section in our obstetrics unit. Sample collection, processing, and laboratory testing were conducted in accordance with the World Health Organization (WHO) guidance. In the next months, conclusive data on obstetrical outcomes concerning the gestational age and pregnancy comorbidity as well as the eventual maternal-fetal transmission are needed.
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Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/transmissão , Transmissão Vertical de Doenças Infecciosas , Placenta/virologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/transmissão , Adulto , COVID-19 , Cesárea , Feminino , Humanos , Pandemias , Gravidez , SARS-CoV-2RESUMO
OBJECTIVES: The primary objective of the study was to compare the performance of the rectal water transvaginal ultrasonography (RWC-TVS) with and without bowel preparation (BP) in diagnosing rectosigmoid endometriosis. The secondary objectives were to compare the performance of the 2 exams in estimating infiltration of the mucosa, length of the largest rectosigmoid nodules, distance of the nodules from the anal verge, and presence of multifocal disease. METHODS: This prospective study included patients with pain symptoms and intestinal complaints suggestive of endometriosis. Patients underwent RWC-TVS with and without BP within an interval of 1 week to 2 months. Two independent and blinded gynecologists performed the exams. The results of the 2 exams were compared with surgical and histologic findings. RESULTS: A total of 155 patients were included in the study; 92 patients had rectosigmoid endometriosis. There was no significant difference in the performance of RWC-TVS with or without BP in diagnosing rectosigmoid endometriosis (P = .727). There was no significant difference in the performance of RWC-TVS with or without BP in diagnosing infiltration of the mucosa (P = .424) and multifocal disease (P = .688), in estimating the main diameter of the largest nodule (P = .644) and the distance between the more distal rectosigmoid nodule and the anal verge (P = .090). The patients similarly tolerated the 2 exams (P = .799). CONCLUSIONS: Bowel preparation does not improve the performance of RWC-TVS in diagnosing rectosigmoid endometriosis and in assessing the characteristics of these nodules.
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Dieta/métodos , Endometriose/diagnóstico por imagem , Enema/métodos , Interpretação de Imagem Assistida por Computador/métodos , Doenças Retais/diagnóstico por imagem , Doenças do Colo Sigmoide/diagnóstico por imagem , Adulto , Colo Sigmoide/diagnóstico por imagem , Feminino , Humanos , Estudos Prospectivos , Reto/diagnóstico por imagem , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Ultrassonografia , ÁguaRESUMO
BACKGROUND/AIMS: Ulipristal acetate ([UPA], Esmya®) is an orally active selective progesterone-receptor modulator that has been approved as preoperative treatment for uterine myomas. This systematic review aims to summarize the available data on surgical outcomes of patients undergoing myomectomy by hysteroscopy or by laparoscopy after preoperative treatment with UPA. METHODS: this review was performed following PRISMA guidelines and was registered in PROSPERO (CRD42018092201). PubMed, EMBASE, and Medline databases were systematically searched electronically until March 2018 for keywords concerning this topic. There were included only peer-reviewed, English language journal articles. RESULTS: two prospective studies and 4 retrospective studies were included. The effect of UPA on the endometrium does not increase the technical difficulty during hysteroscopic myomectomy, but it increases the chance of complete primary resection in complex hysteroscopic myomectomies. Moreover, UPA does not increase the overall technical difficulty of laparoscopic myomectomy. Contradictory results have been reported on the impact of UPA on the separation of the myoma from the myometrium and on the consistency of the myomas. CONCLUSION: current results support the use of UPA prior to both surgical procedures. Further studies should confirm these preliminary findings and to assess the long-term outcomes of myomectomies following UPA treatment.
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Histeroscopia/métodos , Laparoscopia/métodos , Leiomioma/cirurgia , Norpregnadienos/administração & dosagem , Miomectomia Uterina/métodos , Neoplasias Uterinas/cirurgia , Adulto , Endométrio/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Período Pré-Operatório , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
INTRODUCTION: Hepatic hemangiomas (HH) are benign vascular tumors, and when large, may contribute to fetal morbidity/mortality. Chorangiosis is placental villus capillary hypervascularity, probably linked with fetal hypoxia. CASE REPORT: We present a macrosomic stillbirth at 39 + 3 weeks of gestation with congestive heart failure (CHF) and myocardial infarction. A giant right hepatic lobe HH was present, along with placental chorangiosis. CONCLUSION: A common pathogenetic pathway between congenital HH and placental chorangiosis has not been reported. Our case suggests that the effects of HH and chorangiosis increase the risk of late fetal loss due to the high-output CHF.
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Hemangioma/patologia , Neoplasias Hepáticas/patologia , Placenta/patologia , Natimorto/genética , Adulto , Vilosidades Coriônicas/patologia , Feminino , Hemangioma/diagnóstico , Hemangioma Cavernoso/diagnóstico , Hemangioma Cavernoso/patologia , Humanos , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Doenças Placentárias/diagnóstico , Doenças Placentárias/patologia , GravidezRESUMO
Sirtuin 6 (SIRT6) is a sirtuin family member involved in a wide range of physiologic and disease processes, including cancer and glucose homeostasis. Based on the roles played by SIRT6 in different organs, including its ability to repress the expression of glucose transporters and glycolytic enzymes, inhibiting SIRT6 has been proposed as an approach for treating type 2 diabetes mellitus (T2DM). However, so far, the lack of small-molecule Sirt6 inhibitors has hampered the conduct of in vivo studies to assess the viability of this strategy. We took advantage of a recently identified SIRT6 inhibitor, compound 1, to study the effect of pharmacological Sirt6 inhibition in a mouse model of T2DM (i.e., in high-fat-diet-fed animals). The administration of the Sirt6 inhibitor for 10 d was well tolerated and improved oral glucose tolerance, it increased the expression of the glucose transporters GLUT1 and -4 in the muscle and enhanced the activity of the glycolytic pathway. Sirt6 inhibition also resulted in reduced insulin, triglycerides, and cholesterol levels in plasma. This study represents the first in vivo study of a SIRT6 inhibitor and provides the proof-of-concept that targeting SIRT6 may be a viable strategy for improving glycemic control in T2DM.-Sociali, G., Magnone, M., Ravera, S., Damonte, P., Vigliarolo, T., Von Holtey, M., Vellone, V. G., Millo, E., Caffa, I., Cea, M., Parenti, M. D., Del Rio, A., Murone, M., Mostoslavsky, R., Grozio, A., Nencioni, A., Bruzzone S. Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model.
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Intolerância à Glucose/metabolismo , Quinazolinonas/farmacologia , Sirtuínas/antagonistas & inibidores , Animais , Glicemia , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica , Intolerância à Glucose/genética , Células Hep G2 , Humanos , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinazolinonas/química , SulfonamidasRESUMO
BACKGROUND: Ischemia/reperfusion (I/R) injury represents one of the most severe complications in vascular surgery where cross-clamping of the aorta and subsequent visceral ischemia are a recurrent issue. The literature describes a family of nuclear receptors, that is, peroxisome proliferator-activated receptors (PPARs), in particular PPARγ isoform, which are important modulators of vascular inflammation resulting from I/R injury. The aim of our study is to evaluate how PPARγ agonist administration could reduce local and systemic inflammatory response after I/R injury during aortic supraceliac clamping in animal model. METHODS: Our model includes 16 rats divided as follows: 8 rats in the placebo control group (PlacG) were operated on without having been administered of any drugs during the preoperative period, whereas the 8 rats in the pioglitazone group (PioG) were pretreated with pioglitazone. Renal and visceral ischemias were induced in the rats by supraceliac aortic clamping. Rats were sacrificed after surgery, and then, we collected blood samples to measure serum levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) and one of the kidneys and a segment of the liver to perform histological analysis. RESULTS: Considering both cytokines in the PioG, there has been a negative trend in serum concentrations, whereas in the PlacG, we observed an increasing trend. The high standard deviation observed in our study is mainly due to the small population of the cohort. Histologic examination of the kidney showed more severe damage in the placebo group as compared to the PioG with more evident differences in tubular and tubulointerstitial scores. CONCLUSIONS: Our observations show that administering pioglitazone can partially reduce secondary inflammatory response in the ischemic insult especially in endothelial and perivascular tissues.
Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/prevenção & controle , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , PPAR gama/agonistas , Traumatismo por Reperfusão/prevenção & controle , Tiazolidinedionas/farmacologia , Animais , Aorta/fisiopatologia , Aorta/cirurgia , Constrição , Citoproteção , Modelos Animais de Doenças , Inflamação/sangue , Inflamação/patologia , Inflamação/fisiopatologia , Mediadores da Inflamação/sangue , Interleucina-6/sangue , Rim/metabolismo , Rim/patologia , Nefropatias/sangue , Nefropatias/patologia , Nefropatias/fisiopatologia , Fígado/metabolismo , Fígado/patologia , Hepatopatias/sangue , Hepatopatias/patologia , Hepatopatias/fisiopatologia , Masculino , PPAR gama/metabolismo , Pioglitazona , Ratos Sprague-Dawley , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangueRESUMO
Paraganglioma is one of the rarest neoplasms involving the ovary, with only 10 previous reports. We present a case of peritoneal carcinomatosis from primary ovarian paraganglioma and a systematic review of the literature. Clinical information was retrieved from medical records, and a systematic review of the literature was performed according to meta-analysis of observational studies in epidemiology guidelines. A 33-year-old woman presented with a 12-month history of hypertension and weight loss. She was diagnosed with ovarian paraganglioma and was treated with extensive debulking surgery to no residual disease after three cycles of neoadjuvant chemotherapy. She recurred after 6 months and was started on somatostatin-analogue. Following further disease progression with bone metastasis (treated with palliative radiotherapy), a trial with Sunitinib was started. The patient died 30 months after initial diagnosis. Of the cases reported to date, only one had peritoneal metastasis at presentation but none of them had such an ominous prognosis. Ovarian paraganglioma is an extremely rare condition. We report the first case of primary malignant ovarian paraganglioma with an exceptionally aggressive behavior. Clinicopathological correlation with immunohistochemistry is essential to avoid misdiagnosis. A standard treatment is not recommended yet but cytoreductive surgery seems to be a favorable approach to prolong survival.