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It is increasingly recognised that diverse genetic respiratory disorders present as severe pulmonary hypertension (PH) in the neonate and young infant, but many controversies and uncertainties persist regarding optimal strategies for diagnosis and management to maximize long-term outcomes. To better define the nature of PH in the setting of developmental lung disorders (DEVLD), in addition to the common diagnoses of bronchopulmonary dysplasia and congenital diaphragmatic hernia, we established a multidisciplinary group of expert clinicians from stakeholder paediatric specialties to highlight current challenges and recommendations for clinical approaches, as well as counselling and support of families. In this review, we characterise clinical features of infants with DEVLD/DEVLD-PH and identify decision-making challenges including genetic evaluations, the role of lung biopsies, the use of imaging modalities, and treatment approaches. The importance of working with team members from multiple disciplines, enhancing communication and providing sufficient counselling services for families is emphasized to create an interdisciplinary consensus.
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OBJECTIVES: Tissue banking procedures have evolved to keep pace with precision medicine, technology, emerging understanding of racial disparities, and regulatory requirements. However, there is little published guidance regarding strategies to create and maintain a successful biorepository. Our objective is to describe the infrastructure and protocols used by our Gynecologic Oncology Tissue Bank. METHODS: Our Tissue Bank was founded in 1992. In August 2022, internal funding was used to modernize the Tissue Bank. We hired three full-time employees, implemented universal screening of patients treated by gynecologic oncology faculty, updated consenting protocols, and standardized communication with providers. Tumor tissue, blood derivatives, ascites, and pleural fluid were collected from eligible, consenting patients and processed. Patient-derived cell lines and organoids were generated. For quality control purposes, one formalin-fixed, paraffin-embedded (FFPE) sample per tissue site was analyzed by a board-certified pathologist. All samples were labeled and tracked in an OpenSpecimen collection protocol and clinically annotated in a secure database. RESULTS: From August 2022 to October 2023, 227 patients (83% white, 15% Black, 1% Asian) were enrolled and 4249 specimens were collected. Adherent cell lines were generated from 15 patients with ovarian cancer and cell suspensions for organoid generation were collected from 46 patients with ovarian cancer. A recharge center was established to self-sustain the Tissue Bank. Samples have been shared with academic and commercial collaborators. CONCLUSIONS: Our Tissue Bank has enrolled a large number of diverse patients, collected numerous specimen types, and collaborated widely. The procedures described here provide guidance for other institutions establishing similar resources.
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OBJECTIVES: Our study examines if the disease severity profile of our Congenital Diaphragmatic Hernia (CDH) patient cohort adherent to long-term follow-up differs from patients lost to follow-up after discharge and examines factors associated with health care utilization. METHODS: Retrospective review identified CDH survivors born 2005-2019 with index repair at our institution. Primary outcome was long-term follow-up status: "active" or "inactive" according to clinic guidelines. Markers of CDH disease severity including CDH defect classification, oxygen use, tube feeds at discharge, and sociodemographic factors were examined as exposures. RESULTS: Of the 222 included patients, median age [IQR] was 10.2 years [6.7-14.3], 61% male, and 57 (26%) were insured by Medicaid. Sixty-three percent (139/222) of patients were adherent to follow-up. Seventy-six percent of patients discharged on tube feeds had active follow-up compared to 55% of patients who were not, with similar findings for oxygen at discharge (76% vs. 55%). Kaplan-Meier analysis showed patients with smaller defect size had earlier attrition compared to patients with larger defect size. Other race (Hispanic, Asian, Middle Eastern) patients had 2.87 higher odds of attrition compared to white patients (95% CI 1.18-7.0). Medicaid patients had 2.64 higher odds of attrition compared to private insurance (95% CI 1.23-5.66). CONCLUSION: Loss to follow-up was associated with race and insurance type. Disease severity was similar between the active and inactive clinic cohorts. Long-term CDH clinic publications should examine attrition to ensure reported outcomes reflect the discharged population. This study identified important factors to inform targeted interventions for follow-up adherence. LEVEL OF EVIDENCE: Level III.
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Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio , Feminino , Humanos , Reparo de Erro de Pareamento de DNA/genética , Instabilidade de Microssatélites , Neoplasias do Endométrio/genética , Biomarcadores Tumorais , Células Clonais/metabolismo , Proteína 1 Homóloga a MutL/genéticaRESUMO
Ovarian cancer is a fatal gynecologic cancer and the fifth leading cause of cancer death among women in the United States. Developing new drug treatments is crucial to advancing healthcare and improving patient outcomes. Organoids are in-vitro three-dimensional multicellular miniature organs. Patient-derived organoid (PDO) models of ovarian cancer may be optimal for drug screening because they more accurately recapitulate tissues of interest than two-dimensional cell culture models and are inexpensive compared to patient-derived xenografts. In addition, ovarian cancer PDOs mimic the variable tumor microenvironment and genetic background typically observed in ovarian cancer. Here, a method is described that can be used to test conventional and novel drugs on PDOs derived from ovarian cancer tissue and ascites. A luminescence-based adenosine triphosphate (ATP) assay is used to measure viability, growth rate, and drug sensitivity. Drug screens in PDOs can be completed in 7-10 days, depending on the rate of organoid formation and drug treatments.
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Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Organoides/patologia , Microambiente TumoralRESUMO
OBJECTIVE: This multi-center cohort study assessed associations between race, TP53 mutations, p53 expression, and histology to investigate racial survival disparities in endometrial cancer (EC). METHODS: Black and White patients with advanced or recurrent EC with Next Generation Sequencing data in the Endometrial Cancer Molecularly Targeted Therapy Consortium database were identified. Clinicopathologic and treatment variables were summarized by race and compared. Overall survival (OS) and progression-free survival (PFS) among all patients were estimated by the Kaplan-Meier method. Cox proportional hazards models estimated the association between race, TP53 status, p53 expression, histology, and survival outcomes. RESULTS: Black patients were more likely than White patients to have TP53-mutated (N = 727, 71.7% vs 49.7%, p < 0.001) and p53-abnormal (N = 362, 71.1% vs 53.2%, p = 0.003) EC. Patients with TP53-mutated EC had worse PFS (HR 2.73 (95% CI 1.88-3.97)) and OS (HR 2.20 (95% CI 1.77-2.74)) compared to those with TP53-wildtype EC. Patients with p53-abnormal EC had worse PFS (HR 2.01 (95% CI 1.22-3.32)) and OS (HR 1.61 (95% CI 1.18-2.19)) compared to those with p53-wildtype EC. After adjusting for TP53 mutation and p53 expression, race was not associated with survival outcomes. The most frequent TP53 variants were at nucleotide positions R273 (n = 54), R248 (n = 38), and R175 (n = 23), rates of which did not differ by race. CONCLUSIONS: Black patients are more likely to have TP53-mutated and p53-abnormal EC, which are associated with worse survival outcomes than TP53- and p53-wildtype EC. The higher frequency of these subtypes among Black patients may contribute to survival disparities.
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Neoplasias do Endométrio , Proteína Supressora de Tumor p53 , Feminino , Humanos , Estudos de Coortes , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Mutação , Recidiva Local de Neoplasia , Prognóstico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , População Negra/genética , População Branca/genéticaRESUMO
Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The propensity for metastasis within the peritoneal cavity is a driving factor for the poor outcomes associated with this disease, but there is currently no effective therapy targeting metastasis. In this study, we investigate the contribution of stromal cells to ovarian cancer metastasis and identify normal stromal cell expression of the collagen receptor, discoidin domain receptor 2 (DDR2), that acts to facilitate ovarian cancer metastasis. In vivo, global genetic inactivation of Ddr2 impairs the ability of Ddr2-expressing syngeneic ovarian cancer cells to spread throughout the peritoneal cavity. Specifically, DDR2 expression in mesothelial cells lining the peritoneal cavity facilitates tumor cell attachment and clearance. Subsequently, omentum fibroblast expression of DDR2 promotes tumor cell invasion. Mechanistically, we find DDR2-expressing fibroblasts are more energetically active, such that DDR2 regulates glycolysis through AKT/SNAI1 leading to suppressed fructose-1,6-bisphosphatase and increased hexokinase activity, a key glycolytic enzyme. Upon inhibition of DDR2, we find decreased protein synthesis and secretion. Consequently, when DDR2 is inhibited, there is reduction in secreted extracellular matrix proteins important for metastasis. Specifically, we find that fibroblast DDR2 inhibition leads to decreased secretion of the collagen crosslinker, LOXL2. Adding back LOXL2 to DDR2 deficient fibroblasts rescues the ability of tumor cells to invade. Overall, our results suggest that stromal cell expression of DDR2 is an important mediator of ovarian cancer metastasis. IMPLICATIONS: DDR2 is highly expressed by stromal cells in ovarian cancer that can mediate metastasis and is a potential therapeutic target in ovarian cancer.
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Receptor com Domínio Discoidina 2 , Neoplasias Ovarianas , Feminino , Humanos , Receptor com Domínio Discoidina 2/genética , Receptor com Domínio Discoidina 2/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fosforilação , Colágeno/metabolismo , Matriz Extracelular/metabolismoRESUMO
High-grade serous ovarian cancer (HGSC) is the most lethal histotype of ovarian cancer and the majority of cases present with metastasis and late-stage disease. Over the last few decades, the overall survival for patients has not significantly improved, and there are limited targeted treatment options. We aimed to better characterize the distinctions between primary and metastatic tumors based on short- or long-term survival. We characterized 39 matched primary and metastatic tumors by whole exome and RNA sequencing. Of these, 23 were short-term (ST) survivors (overall survival (OS) < 3.5 years) and 16 were long-term (LT) survivors (OS > 5 years). We compared somatic mutations, copy number alterations, mutational burden, differential gene expression, immune cell infiltration, and gene fusion predictions between the primary and metastatic tumors and between ST and LT survivor cohorts. There were few differences in RNA expression between paired primary and metastatic tumors, but significant differences between the transcriptomes of LT and ST survivors in both their primary and metastatic tumors. These findings will improve the understanding of the genetic variation in HGSC that exist between patients with different prognoses and better inform treatments by identifying new targets for drug development.
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Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Prognóstico , Variações do Número de Cópias de DNARESUMO
TOPIC IMPORTANCE: Postacute sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from COVID-19. Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood. REVIEW FINDINGS: Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms. SUMMARY: This review illustrates exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.
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COVID-19 , Síndrome de Fadiga Crônica , Humanos , Síndrome de Fadiga Crônica/etiologia , SARS-CoV-2 , Exercício Físico/fisiologia , Teste de EsforçoRESUMO
PURPOSE: To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples. EXPERIMENTAL DESIGN: RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n = 5), organoids (n = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery n = 31, validation n = 148). Samples were defined as RAD51-High if >10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated. RESULTS: RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r = 0.96, P = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P < 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; P < 0.001) and to be platinum-sensitive (RR, ∞; P = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78-1.0; P < 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; P < 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33-0.85; P < 0.001) and overall survival (HR, 0.43; 95% CI, 0.25-0.75; P = 0.003) than RAD51-High status. CONCLUSIONS: RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.
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Neoplasias Ovarianas , Platina , Humanos , Feminino , Platina/uso terapêutico , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Biomarcadores Tumorais/uso terapêuticoRESUMO
Immunofluorescence is one of the most widely used techniques to visualize target antigens with high sensitivity and specificity, allowing for the accurate identification and localization of proteins, glycans, and small molecules. While this technique is well-established in two-dimensional (2D) cell culture, less is known about its use in three-dimensional (3D) cell models. Ovarian cancer organoids are 3D tumor models that recapitulate tumor cell clonal heterogeneity, the tumor microenvironment, and cell-cell and cell-matrix interactions. Thus, they are superior to cell lines for the evaluation of drug sensitivity and functional biomarkers. Therefore, the ability to utilize immunofluorescence on primary ovarian cancer organoids is extremely beneficial in understanding the biology of this cancer. The current study describes the technique of immunofluorescence to detect DNA damage repair proteins in high-grade serous patient-derived ovarian cancer organoids (PDOs). After exposing the PDOs to ionizing radiation, immunofluorescence is performed on intact organoids to evaluate nuclear proteins as foci. Images are collected using z-stack imaging on confocal microscopy and analyzed using automated foci counting software. The described methods allow for the analysis of temporal and special recruitment of DNA damage repair proteins and colocalization of these proteins with cell-cycle markers.
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Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Linhagem Celular , Cistadenocarcinoma Seroso/patologia , Dano ao DNA , Organoides/metabolismo , Microambiente TumoralRESUMO
A male infant presented at term with neonatal respiratory failure and pulmonary hypertension. His respiratory symptoms improved initially, but he exhibited a biphasic clinical course, re-presenting at 15 months of age with tachypnea, interstitial lung disease, and progressive pulmonary hypertension. We identified an intronic TBX4 gene variant in close proximity to the canonical donor splice site of exon 3 (hg 19; chr17:59543302; c.401 + 3 A > T), also carried by his father who had a typical TBX4-associated skeletal phenotype and mild pulmonary hypertension, and by his deceased sister who died shortly after birth of acinar dysplasia. Analysis of patient-derived cells demonstrated a significant reduction in TBX4 expression resulting from this intronic variant. Our study illustrates the variable expressivity in cardiopulmonary phenotype conferred by TBX4 mutation and the utility of genetic diagnostics in enabling accurate identification and classification of more subtly affected family members.
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Organoids are 3D dynamic tumor models that can be grown successfully from patient-derived ovarian tumor tissue, ascites, or pleural fluid and aid in the discovery of novel therapeutics and predictive biomarkers for ovarian cancer. These models recapitulate clonal heterogeneity, the tumor microenvironment, and cell-cell and cell-matrix interactions. Additionally, they have been shown to match the primary tumor morphologically, cytologically, immunohistochemically, and genetically. Thus, organoids facilitate research on tumor cells and the tumor microenvironment and are superior to cell lines. The present protocol describes distinct methods to generate patient-derived ovarian cancer organoids from patient tumors, ascites, and pleural fluid samples with a higher than 97% success rate. The patient samples are separated into cellular suspensions by both mechanical and enzymatic digestion. The cells are then plated utilizing a basement membrane extract (BME) and are supported with optimized growth media containing supplements specific to the culturing of high-grade serous ovarian cancer (HGSOC). After forming initial organoids, the PDOs can sustain long-term culture, including passaging for expansion for subsequent experiments.
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Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Ascite/patologia , Neoplasias Ovarianas/patologia , Cistadenocarcinoma Seroso/patologia , Carcinoma Epitelial do Ovário/patologia , Organoides/patologia , Microambiente TumoralRESUMO
OBJECTIVE: To examine the impact of race/ethnicity on timing and postoperative outcomes of primary cleft lip (CL) and cleft palate (CP) repair. DESIGN: Cross-sectional analysis of the National Surgical Quality Improvement Program Pediatric (NSQIP-P) database from 2013 to 2018. PATIENTS AND MAIN OUTCOME MEASURES: Patients under 2 years of age who underwent primary CL or CP repair were identified in the NSQIP-P. Outcomes were the timing of surgery and 30-day readmission and reoperation rates stratified by race and ethnicity. RESULTS: In total, 6021 children underwent CL and 6938 underwent CP repair. Adjusted rates of CL repair over time were 10% lower in Hispanic children (95%CI: 0.84-0.96) and 38% lower for Asian children (95%CI: 0.55-0.70) compared with White infants. CP repair rates over time were 13% lower in Black (95%CI: 0.79-0.95), 17% lower in Hispanic (95%CI: 0.77-0.89), and 53% lower in Asian children (95%CI: 0.43-0.53) than in White infants. Asian patients had the highest rates of delayed surgical repair, with 19.3% not meeting American Cleft Palate-Craniofacial Association (ACPA) guidelines for CL (P < .001) and 28.2% for CP repair (P< .001). Black and Hispanic children had 80% higher odds of readmission following primary CL repair (95%CI: 1.16-2.83 and 95%CI: 1.27-2.61, respectively). CONCLUSIONS: This study of a national database identified several racial/ethnic disparities in primary CL and CP, with reduced receipt of cleft repair over time for non-White children. Asian patients were significantly more likely to have delayed cleft repair per ACPA guidelines. These findings underscore the need to better understand disparities in cleft repair timing and postoperative outcomes.
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Fenda Labial , Fissura Palatina , Lactente , Humanos , Criança , Estados Unidos , Fissura Palatina/cirurgia , Fenda Labial/cirurgia , Estudos Transversais , Reoperação , Complicações Pós-Operatórias/cirurgiaRESUMO
Immune-mediated bile duct epithelial injury and toxicity of retained hydrophobic bile acids drive disease progression in fibrosing cholangiopathies such as biliary atresia or primary sclerosing cholangitis. Emerging therapies include pharmacological agonists to farnesoid X receptor (FXR), the master regulator of hepatic synthesis, excretion, and intestinal reuptake of bile acids. Unraveling the mechanisms of action of pharmacological FXR agonists in the treatment of sclerosing cholangitis (SC), we found that intestinally restricted FXR activation effectively reduced bile acid pool size but did not improve the SC phenotype in MDR2-/- mice. In contrast, systemic FXR activation not only lowered bile acid synthesis but also suppressed proinflammatory cytokine production by liver-infiltrating inflammatory cells and blocked progression of hepatobiliary injury. The hepatoprotective activity was linked to suppressed production of IL1ß and TNFα by hepatic macrophages and inhibition of TH1/TH17 lymphocyte polarization. Deletion of FXR in myeloid cells caused aberrant TH1 and TH17 lymphocyte responses in diethoxycarbonyl-1,4-dihydrocollidine-induced SC and rendered these mice resistant to the anti-inflammatory and liver protective effects of systemic FXR agonist treatment. Pharmacological FXR activation reduced IL1ß and IFNγ production by liver- and blood-derived mononuclear cells from patients with fibrosing cholangiopathies. In conclusion, we demonstrate FXR to control the macrophage-TH1/17 axis, which is critically important for the progression of SC. Hepatic macrophages are cellular targets of systemic FXR agonist therapy for cholestatic liver disease.
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Colangite Esclerosante , Camundongos , Animais , Colangite Esclerosante/tratamento farmacológico , Linfócitos T , Ácidos e Sais Biliares , Fígado , MacrófagosRESUMO
Objective: Given the importance of understanding neighborhood context and geographic access to care on individual health outcomes, we sought to investigate the association of community primary care (PC) access on postoperative outcomes and survival in ovarian cancer patients. Methods: This was a retrospective cohort study of Stage III-IV ovarian cancer patients who underwent surgery at a single academic, tertiary care hospital between 2012 and 2015. PC access was determined using a Health Resources and Services Administration designation. Outcomes included 30-day surgical and medical complications, extended hospital stay, ICU admission, hospital readmission, progression-free and overall survival. Descriptive statistics and chi-squared analyses were used to analyze differences between patients from PC-shortage vs not PC-shortage areas. Results: Among 217 ovarian cancer patients, 54.4 % lived in PC-shortage areas. They were more likely to have Medicaid or no insurance and live in rural areas with higher poverty rates, significantly further from the treating cancer center and its affiliated hospital. Nevertheless, 49.2 % of patients from PC-shortage areas lived in urban communities. Residing in a PC-shortage area was not associated with increased surgical or medical complications, ICU admission, or hospital readmission, but was linked to more frequent prolonged hospitalization (26.3 % vs 14.1 %, p = 0.04). PC-shortage did not impact progression-free or overall survival. Conclusions: Patients from PC-shortage areas may require longer inpatient perioperative care in order to achieve the same 30-day postoperative outcomes as patients who live in non-PC shortage areas. Community access to PC is a critical factor to better understanding and reducing disparities among ovarian cancer patients.
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OBJECTIVES: Visceral adiposity has been established as a predictor of outcomes in various cancers. We aimed to determine the association of radiographic measurements of visceral fat with clinical outcomes in patients with endometrial cancer. METHODS: A retrospective review of patients with stage III-IV endometrial cancer who underwent surgery between 2004 and 2014 was performed. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and total adipose tissue (TAT;VAT+SAT) were assessed on preoperative computed tomography (CT) scans. Exploratory analysis was performed to establish the optimal cut-off values for VAT, SAT, and TAT to identify patients with poor prognostic body composition. Survival rates were analyzed using Kaplan-Meier analysis, log-rank tests, and cox-regression. RESULTS: Eighty-three patients were included. Forty-two (51%) patients had a low VAT/SAT ratio (<0.45) and 41 (49.4%) had a high VAT/SAT ratio (>0.45). There were no significant differences in demographics between the groups. The mean VAT, SAT, and TAT were 176.3 cm2, 379.3 cm2, and 555.3 cm2 respectively. Compared to patients with low VAT/SAT ratios, patients with high VAT/SAT ratios had a shorter recurrence-free survival (median 29.6 vs 32.3 months, P = 0.01) and shorter overall survival (median 56 vs 93.7 months, P = 0.03). CONCLUSIONS: Visceral fat measurements are predictive of outcomes in patients with advanced stage endometrial cancer. Specifically, VAT to SAT ratios are predictive of overall survival. Future studies should be pursued to identify potential therapeutic targets and biological mechanisms that underlie obesity's relationship with endometrial cancer.
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Neoplasias do Endométrio , Gordura Intra-Abdominal , Humanos , Feminino , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/metabolismo , Gordura Subcutânea/diagnóstico por imagem , Composição Corporal , Tomografia Computadorizada por Raios X , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/cirurgia , Neoplasias do Endométrio/metabolismoRESUMO
Chemotherapy is often ineffective in advanced-stage and aggressive histologic subtypes of endometrial cancer. Overexpression of the receptor tyrosine kinase AXL has been found to be associated with therapeutic resistance, metastasis, and poor prognosis. However, the mechanism of how inhibition of AXL improves response to chemotherapy is still largely unknown. Thus, we aimed to determine whether treatment with AVB-500, a selective inhibitor of GAS6-AXL, improves endometrial cancer cell sensitivity to chemotherapy particularly through metabolic changes. We found that both GAS6 and AXL expression were higher by immunohistochemistry in patient tumors with a poor response to chemotherapy compared with tumors with a good response to chemotherapy. We showed that chemotherapy-resistant endometrial cancer cells (ARK1, uterine serous carcinoma and PUC198, grade 3 endometrioid adenocarcinoma) had improved sensitivity and synergy with paclitaxel and carboplatin when treated in combination with AVB-500. We also found that in vivo intraperitoneal models with ARK1 and PUC198 cells had decreased tumor burden when treated with AVB-500 + paclitaxel compared with paclitaxel alone. Treatment with AVB-500 + paclitaxel decreased AKT signaling, which resulted in a decrease in basal glycolysis. Finally, multiple glycolytic metabolites were lower in the tumors treated with AVB-500 + paclitaxel than in tumors treated with paclitaxel alone. Our study provides strong preclinical rationale for combining AVB-500 with paclitaxel in aggressive endometrial cancer models.
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Antineoplásicos , Neoplasias do Endométrio , Antineoplásicos/farmacologia , Neoplasias do Endométrio/metabolismo , Feminino , Glicólise , Humanos , Paclitaxel , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismoRESUMO
Chronic pulmonary hypertension of infancy (cPHi) is a heterogeneous disease process that contributes to morbidity and mortality in preterm infants. cPHi is most commonly associated with chronic lung disease of prematurity and represents a unique phenotype of bronchopulmonary dysplasia. It is characterized by persistently elevated or newly rising pulmonary vascular resistance and pulmonary artery pressure beyond the first weeks of age. The high-pressure afterload on the right ventricle may or may not be tolerated, depending upon additional cardiovascular shunting and co-morbidities. A comprehensive clinical evaluation combined with advanced hemodynamic assessment by echocardiography and other cardiac imaging modalities help decipher the etiopathologies of disease, identify cardiopulmonary compromise earlier and guide individualized therapeutic intervention tailored by the phenotype. This review summarizes the underlying etiologies, risk factors for development, hemodynamic assessment, management, and follow-up of cPHi in preterm infants. We offer an algorithm for early detection of cPHi and outline research priorities.
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Displasia Broncopulmonar , Hipertensão Pulmonar , Doenças do Prematuro , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/diagnóstico , Displasia Broncopulmonar/terapia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Recém-Nascido , Recém-Nascido Prematuro , PulmãoRESUMO
Background: Biomarkers are increasingly part of assessing and managing heart failure (HF) in adults with congenital heart disease (CHD). Objectives: To understand the response of cardiac biomarkers with therapy for acute decompensated heart failure (ADHF) and the relationship to prognosis after discharge in adults with CHD. Design: A prospective, observational cohort study with serial blood biomarker measurements. Settings: Single-center study in the inpatient setting with outpatient follow-up. Participants: Adults (≥18 years old) with CHD admitted with ADHF between August 1, 2019, and March 1, 2020. Exposure: We measured body mass, Kansas City Cardiomyopathy Questionnaire (KCCQ-12) score, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) at enrollment, discharge, and 1st clinic follow-up visit; soluble suppression of tumorigenicity 2 (sST2) was measured at the first two time points. Measures: Univariate regression assessed the association between changes in weight, biomarkers, and changes in KCCQ-12 scores, between enrollment and discharge (Δ Hospitalization ) and between discharge and 1st clinical follow-up visit (Δ Post-discharge ). Wilcoxon rank-sum tests assessed the association between change in biomarkers, KCCQ-12 scores, and the composite outcome of cardiovascular death or rehospitalization for ADHF. Results: A total of 26 patients were enrolled. The median age was 51.9 years [IQR: 38.8, 61.2], 13 (54.2%) were women, and median hospital stay was 6.5 days [IQR: 4.0, 15.0] with an associated weight loss of 2.8 kg [IQR -5.1, -1.7]. All three cardiac biomarkers decreased during hospitalization with diuresis while KCCQ-12 scores improved; a greater decrease in sST2 was associated with an improved KCCQ-12 symptom frequency (SF) subdomain score (p = 0.012), but otherwise, there was no significant relationship between biomarkers and KCCQ-12 change. Change in hsCRP and NT-proBNP after discharge was not associated with the composite outcome (n = 8, vs. n = 16 who did not experience the outcome; Δ Post-discharge hsCRP +5.1 vs. -1.0 mg/l, p = 0.061; NT-proBNP +785.0 vs. +130.0 pg/ml, p = 0.220). Conclusions: Serial biomarker measurements respond to acute diuresis in adults with CHD hospitalized for ADHF. These results should motivate further research into the use of biomarkers to inform HF therapy in adults with CHD.