Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-32176177

RESUMO

BACKGROUND: The Emergency Surgery Score (ESS) was recently developed and retrospectively validated as an accurate mortality risk calculator for Emergency General Surgery (EGS). We sought to prospectively validate ESS, specifically in the high-risk non-trauma emergency laparotomy (EL) patient. METHODS: This is an EAST multicenter prospective observational study. Between April 2018 and June 2019, 19 centers enrolled all adults (age >18 years) undergoing EL. Preoperative, intraoperative, and postoperative variables were prospectively and systematically collected. ESS was calculated for each patient and validated using c-statistic methodology by correlating it with three postoperative outcomes: 1) 30-day mortality, 2) 30-day complications (e.g. respiratory/renal failure, infection), and 3) postoperative ICU admission. RESULTS: A total of 1,649 patients were included. The mean age was 60.5 years, 50.3% were female, and 71.4% were white. The mean ESS was 6, and the most common indication for EL was hollow viscus perforation. The 30-day mortality and complication rates were 14.8% and 53.3%; 57.0% of patients required ICU admission. ESS gradually and accurately predicted 30-day mortality; 3.5%, 50.0% and 85.7% of patients with ESS of 3, 12 and 17 died after surgery, respectively with a c-statistic of 0.84. Similarly, ESS gradually and accurately predicted complications; 21.0%, 57.1% and 88.9% of patients with ESS of 1, 6 and 13 developed postoperative complications, with a c-statistic of 0.74. ESS also accurately predicted which patients required ICU admission (c-statistic 0.80). CONCLUSIONS: This is the first prospective multicenter study to validate ESS as an accurate predictor of outcome in the EL patient. ESS can prove useful for 1) perioperative patient and family counseling, 2) triaging patients to the ICU and 3) benchmarking the quality of EGS care. LEVEL OF EVIDENCE: Prognostic study, level III.

2.
J Surg Res ; 245: 163-167, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419641

RESUMO

BACKGROUND: The Advanced Trauma Life Support (ATLS) shock classification has been accepted as the conceptual framework for clinicians caring for trauma patients. We sought to validate its ability to predict mortality, blood transfusion, and urgent intervention. MATERIALS AND METHODS: We performed a retrospective review of trauma patients using the 2014 National Trauma Data Bank. Using initial vital signs data, patients were categorized into shock class based on the ATLS program. Rates for urgent blood transfusion, urgent operative intervention, and mortality were compared between classes. RESULTS: 630,635 subjects were included for analysis. Classes 1, 2, 3, and 4 included 312,404, 17,133, 31, and 43 patients, respectively. 300,754 patients did not meet criteria for any ATLS shock class. Of the patients in class 1 shock, 2653 died (0.9%), 3123 (1.0%) were transfused blood products, and 7115 (2.3%) underwent an urgent procedure. In class 2, 219 (1.3%) died, 387 (2.3%) were transfused, and 1575 (9.2%) underwent intervention. In class 3, 7 (22.6%) died, 10 (32.3%) were transfused, and 13 (41.9%) underwent intervention. In class 4, 15 (34.9%) died, 19 (44.2%) were transfused, and 23 (53.5%) underwent intervention. For uncategorized patients, 21,356 (7.1%) died, 15,168 (5.0%) were transfused, and 23,844 (7.9%) underwent intervention. CONCLUSIONS: Almost half of trauma patients do not meet criteria for any ATLS shock class. Uncategorized patients had a higher mortality (7.1%) than patients in classes 1 and 2 (0.9% and 1.3%, respectively). Classes 3 and 4 only accounted for 0.005% and 0.007%, respectively, of patients. The ATLS classification system does not help identify many patients in severe shock.


Assuntos
Cuidados de Suporte Avançado de Vida no Trauma/normas , Medição de Risco/métodos , Choque/classificação , Índices de Gravidade do Trauma , Ferimentos e Lesões/complicações , Adulto , Idoso , Transfusão de Sangue/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Choque/diagnóstico , Choque/etiologia , Choque/mortalidade , Análise de Sobrevida , Ferimentos e Lesões/diagnóstico , Ferimentos e Lesões/mortalidade , Ferimentos e Lesões/terapia , Adulto Jovem
3.
Artigo em Inglês | MEDLINE | ID: mdl-31687887

RESUMO

Objective: To compare the presentation, management, and outcomes of appendicitis in pregnant and non-pregnant females of childbearing age (18-45 years). Methods: This was a post-hoc analysis of a prospectively collected database (January 2017-June 2018) from 28 centers in America. We compared pregnant and non-pregnant females' demographics, clinical presentation, laboratory data, imaging findings, management, and clinical outcomes. Results: Of the 3,597 subjects, 1,010 (28%) were of childbearing age, and 41 were pregnant: The mean age of the pregnant subjects was 30 ± 8 years at a median gestational age of 15 (range 10-23) weeks. The two groups had similar demographics and clinical presentation, but there were differences in management and outcomes. For example, in pregnant subjects, abdominal ultrasound scans (US) plus magnetic resonance imaging (MRI) was the most frequently used imaging method (41%) followed by MRI alone (29%), US alone (22%), computed tomography (CT) (5%), and no imaging (2%). Despite similar American Association for the Surgery of Trauma Emergency General Surgery Clinical and Imaging Grade at presentation, pregnant subjects were more likely to be treated with antibiotics alone (15% versus 4%; p = 0.008). Pregnant subjects were less likely to have simple appendicitis and were more likely to have complicated (perforated or gangrenous) appendicitis or a normal appendix. With the exception of index hospital length of stay, there were no significant differences between the groups in clinical outcomes at index hospitalization or at 30 days. Conclusion: Almost 1 in 20 women of childbearing age presenting with appendicitis is pregnant. Appendicitis most commonly affects women in early to mid-pregnancy. Compared with non-pregnant women of childbearing age, pregnant women presenting with appendicitis undergo non-operative management more often and are less likely to have simple appendicitis. Compared with non-pregnant patients, they have similar clinical outcomes at both index hospitalization and 30 days after discharge.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31602681

RESUMO

BACKGROUND: Previous studies have used using Indirect Calorimetry (IC) with solitary or sparse measurements of resting energy expenditure (REE). This "snapshot" may not capture the dynamic nature of metabolic requirements. Using continuous IC, we describe the variation of REE during the first days in the intensive care unit. METHODS: Injured adults (≥18 years) requiring mechanical ventilation from March 2018 to September 2018 were enrolled. IC was initiated within 4 days of admission and continuous REE recorded until 14 days, extubation, or death. Multiple 10-minute periods collected during steady state were used to calculate daily REE maximum, minimum, average, and variability [(REEmax - REEmin/2)/average REE]. RESULTS: We included 55 patients. Median age was 38 [27-58] years, 38 (69%) were male, body mass index was 28 [25-33] kg/m2 , and Acute Physiology and Chronic Health Evaluation II was 17 [14-24]. Mechanism of injury was: blunt (n = 38, 69%), penetrating (n = 9, 16%), and burn (n = 8, 15%). Average REE increased gradually from 1,663 kcal [1,435-2,143] to a maximum of 2,080 [1,701-2,336] on day 7, a relative 25% increase, which was sustained through day 14. REE variability ranged 8%-13% and was not reliably predicted by fever, tachycardia, elevated intracranial pressures, hypertension, or hypotension. CONCLUSION: In critically injured patients, steady-state REE measurements display fluctuations over a 24-hour period and demonstrate a gradual rise over the first few days after injury. Continuous REE, if available, is recommended for more precise matching of energy delivery to metabolic requirements.

5.
Prenat Diagn ; 39(12): 1136-1147, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31498910

RESUMO

OBJECTIVE: 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies. METHODS: Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. RESULTS: In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA-binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B-associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum. CONCLUSIONS: We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making.

6.
Nutr Clin Pract ; 2019 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-31423668

RESUMO

BACKGROUND: Overfeeding and underfeeding are associated with poor clinical outcomes. In the absence of indirect calorimetry (IC), the Society of Critical Care Medicine/ASPEN recommend prescribing 25-30 kcal/kg. The Harris-Benedict equation (HBE) multiplied by a stress factor is commonly applied in critically ill patients. We describe the difference between estimated and actual energy needs in critically injured patients. METHODS: From March to November 2018, we collected demographics and energy needs determined by continuous IC (started within 4 days) in intubated adults. Ideal or adjusted body weight was used for 25-30 kcal/kg, and HBE was multiplied by a 1.3 stress factor (1.3HBE). Daily requirements up to 14 days, extubation, or death were calculated using all 3 methods and compared with IC. RESULTS: Fifty-five subjects were included. Median age was 38 [27-58] years, 38 (69%) were male, body mass index was 28 [25-33] kg/m2 , and Acute Physiology and Chronic Health Evaluation II score was 17 [14-24] Mechanism of injury was blunt (38, 69%), penetrating (9, 16%), and burn (8, 15%). By day 14, compared with measured energy requirements by IC, the other methods could result in a cumulative 1827-kcal (+7%) surplus (1.3HBE), a 1313-kcal (-5%) deficit (25 kcal/kg), or a 3950-kcal (+14%) surplus (30 kcal/kg) per patient over a median 9 days. CONCLUSION: In critically injured patients, predictive equations for energy needs do not account for dynamic metabolic changes over time and could result in underfeeding or overfeeding. Adjusting daily prescription based on continuous IC may result in better individualized treatment.

7.
J Trauma Acute Care Surg ; 87(1): 134-139, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31259871

RESUMO

BACKGROUND: The American Association for the Surgery of Trauma (AAST) has proposed a grading system for anatomic severity of 16 Emergency General Surgery conditions, including appendicitis. This is the first prospective, multicenter clinical study evaluating the AAST Appendicitis grading scale. METHODS: The EAST Appendicitis study utilized data collected prospectively from 27 centers, between January 2017 to June 2018. An overall grade was assigned as the highest grade of the subscales: clinical, radiographic, operative, and pathologic. Grade 1-3 of the clinical subscale was assigned as Grade 1. Patients with a final diagnosis other than appendicitis were excluded. The cohort was divided into two groups: simple appendicitis (Grades 1 and 2), and complicated appendicitis (Grades 3, 4, and 5).Fisher's exact and Kruskal-Wallis tests were used to determine association between the overall AAST grade and the following outcomes: infectious complications, Clavien-Dindo complications, hospital length of stay (LOS), 30-day emergency department visits, readmissions, and secondary interventions. RESULTS: A total of 2,909 cases were analyzed: 1,656 (57%) were Grade 1; 181 (6%), Grade 2; 399 (14%) Grade 4; and 549 (19%) Grade 5; 94% of patients underwent appendectomy. Index hospitalization LOS increased significantly with increasing grade: 1, [1,1], 1 [1,2], 1 [1,2], 2 [1,3], and 32,5 (p < 0.001). Infectious complications, Clavien-Dindo complications, hospital LOS, and secondary interventions were significantly associated with increasing AAST severity grade during index hospitalization. For 30-day outcomes, similar trends were noted for readmission, 30-day infections complications, 30-day cumulative infectious complications, 30-day Clavien-Dindo complications, 30-day cumulative Clavien-Dindo complications, 30-day secondary interventions, and 30-day cumulative secondary interventions. CONCLUSION: The AAST emergency general surgery grade for appendicitis is a valid predictor of clinical outcomes such as infectious complications, overall complications, and the need for secondary intervention. LEVEL OF EVIDENCE: Prognostic, level III.


Assuntos
Apendicite/patologia , Índice de Gravidade de Doença , Adulto , Apendicite/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Sociedades Médicas/normas , Estados Unidos , Adulto Jovem
8.
J Surg Res ; 243: 23-26, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31151033

RESUMO

BACKGROUND: It is commonly taught that a widened mediastinum (WM) on chest X-ray (CXR) is a marker for aortic injury (AI). We sought to describe the epidemiology of injuries for all patients with WM and compare their CXR to those of patients with confirmed AI. METHODS: Adults (age ≥ 18) sustaining blunt traumatic injuries from January 2017 to June 2017 with both CXR (supine, anterior-posterior) and chest CT were included. We excluded those whose CT preceded CXR and those with missing data. Basic demographics, injury characteristics, mediastinal width (MW), mediastinal-to-thoracic width ratio (MTR), and all thoracic imaging findings were analyzed. MW > 8 cm was considered WM. We also queried our registry for all AI patients over a 4-year period. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of WM on CXR for AI were calculated. Multivariate logistic regression was performed to identify factors associated with positive traumatic findings, controlling for body mass index (BMI), sex, high-energy mechanism, MTR, and mediastinal width. RESULTS: Of 749 included subjects, 502 (67%) had an MW > 8 cm: mean age was 48 ± 20 y, 381 (76%) were men, and BMI was 28 ± 5 kg/m2. Mechanism of injury was motor vehicle crash in 335 (67%); fall in 113 (23%); assault in 31 (6%); other (jet-ski accidents, etc.) in 17 (3%), and unknown in 6 (1%). Only 128 (26%) of patients with WM had positive findings on CT, with the most common [80 (16%)] being nontraumatic findings (pericardial infusion, lymph nodes, etc.), followed by hemomediastinum/pneumomediastinum [32 (6%)], sternal fractures [18 (4%)], multiple findings [15 (3%)], and vertebral fractures [6 (1%)]. Only 2 (1%) had AI. The sensitivity was 100%, specificity was 33%, PPV was 0.4%, NPV was 100%, and accuracy was 33%. From 2013 to 2017, 38 patients had AI: mean age was 46 ± 19 y, 26 (68%) were men, and BMI was 28 ± 4 kg/m2. Motor vehicle crash was the most common mechanism (89%), followed by "other" trauma mechanism (5%), fall (3%), and assault (3%). On univariate analysis, compared with all patients with WM, patients with AI had significantly greater MW (9.5 [8.8-10.4] versus 10.2 [9.1-11.1]; P = 0.042) and MTR (0.31 [0.28-0.34] versus 0.32 [0.31-0.37]; P = 0.001), although the actual differences were not clinically significant. The regression analysis did not identify any factors associated with traumatic CXR findings. CONCLUSIONS: Most bluntly injured adults have a WM, and the majority have either no findings or nontraumatic findings. The PPV of a WM for AI is <1%. WM on supine CXR is nonspecific and inaccurate for diagnosing traumatic injuries, especially AI.


Assuntos
Aorta/lesões , Mediastino/diagnóstico por imagem , Traumatismos Torácicos/diagnóstico por imagem , Lesões do Sistema Vascular/diagnóstico por imagem , Ferimentos não Penetrantes/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Radiografia Torácica , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X , Lesões do Sistema Vascular/etiologia
9.
Genet Med ; 21(12): 2723-2733, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31239556

RESUMO

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

10.
Int J Cancer ; 145(4): 941-951, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30694527

RESUMO

Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified. The tumors showed an epithelial-type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss-of-heterozygosity (LOH) of the TRIM28-locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial-type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.


Assuntos
Haploinsuficiência/genética , Proteína 28 com Motivo Tripartido/genética , Tumor de Wilms/genética , Carcinogênese/genética , Pré-Escolar , DNA de Neoplasias/genética , Feminino , Genes do Tumor de Wilms/fisiologia , Predisposição Genética para Doença/genética , Genótipo , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Lactente , Neoplasias Renais/genética , Mutação com Perda de Função/genética , Perda de Heterozigosidade/genética , Masculino , Sequenciamento Completo do Exoma/métodos
11.
Liver Transpl ; 25(3): 380-387, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30548128

RESUMO

Detrimental consequences of hypofibrinolysis, also known as fibrinolysis shutdown (FS), have recently arisen, and its significance in liver transplantation (LT) remains unknown. To fill this gap, this retrospective study included 166 adults who received transplants between 2016 and 2018 for whom baseline thromboelastography was available. On the basis of percent of clot lysis 30 minutes after maximal amplitude, patients were stratified into 3 fibrinolysis phenotypes: FS, physiologic fibrinolysis, and hyperfibrinolysis. FS occurred in 71.7% of recipients, followed by physiologic fibrinolysis in 19.9% and hyperfibrinolysis in 8.4%. Intraoperative and postoperative venous thrombosis events occurred exclusively in recipients with the FS phenotype. Intraoperative thrombosis occurred with an overall incidence of 4.8% and was associated with 25.0% in-hospital mortality. Incidence of postoperative venous thrombosis within the first month was deep venous thrombosis/pulmonary embolism (PE; 4.8%) and portal vein thrombosis/hepatic vein thrombosis (1.8%). Massive transfusion of ≥20 units packed red blood cells was required in 11.8% of recipients with FS compared with none in the other 2 phenotype groups (P = 0.01). Multivariate analysis identified 2 pretransplant risk factors for FS: platelet count and nonalcoholic steatohepatitis/cryptogenic cirrhosis. Recursive partitioning identified a critical platelet cutoff value of 50 × 109 /L to be associated with FS phenotype. The hyperfibrinolysis phenotype was associated with the lowest 1-year survival (85.7%), followed by FS (95.0%) and physiologic fibrinolysis (97.0%). Infection/multisystem organ failure was the predominant cause of death; in the FS group, 1 patient died of exsanguination, and 1 patient died of massive intraoperative PE. In conclusion, there is a strong association between FS and thrombohemorrhagic complications and poorer outcomes after LT.

12.
Am J Med Genet A ; 179(1): 50-56, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30548383

RESUMO

Biallelic variants in the AEBP1 gene cause a novel autosomal-recessive connective tissue disorder (CTD) reminiscent of Ehlers-Danlos Syndrome (EDS). The four previously reported individuals show considerable clinical variability. Unbiased high-throughput sequencing enables the rapid identification of additional cases for such rare entities. We identified the homozygous nonsense variant c.917dup, p.Tyr306* in AEBP1 using clinical exome sequencing in a female individual with previously unsolved CTD. Segregation testing confirmed homozygosity in the clinically affected brother and heterozygous carrier status in the healthy mother. Chromosomal microarray showed that the variant lies in a run of homozygosity, suggesting a common origin of this genomic segment. RT-PCR analysis in the mother revealed a monoallelic expression of the normal transcript supporting a nonsense-mediated mRNA decay and functional nullizygosity as disease mechanism. We describe two individuals from a fourth family with AEBP1-associated CTD. Our results further verify that autosomal-recessive inherited LOF variants in the AEBP1 gene cause clinical features of different EDS subtypes, but also of the marfanoid spectrum. As identification of further individuals is necessary to inform the clinical characterization, we stress the added value of exome sequencing for such rare diseases.


Assuntos
Carboxipeptidases/genética , Doenças do Tecido Conjuntivo/genética , Síndrome de Ehlers-Danlos/genética , Predisposição Genética para Doença , Proteínas Repressoras/genética , Adulto , Códon sem Sentido/genética , Tecido Conjuntivo/metabolismo , Tecido Conjuntivo/patologia , Doenças do Tecido Conjuntivo/fisiopatologia , Síndrome de Ehlers-Danlos/fisiopatologia , Exoma/genética , Feminino , Genes Recessivos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Mutação com Perda de Função/genética , Masculino , Linhagem , Fenótipo , Irmãos
13.
BMC Cancer ; 18(1): 926, 2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30257646

RESUMO

BACKGROUND: Breast cancer is the most common cancer in women. 12-15% of all tumors are triple-negative breast cancers (TNBC). So far, TNBC has been mainly associated with mutations in BRCA1. The presence of other predisposing genes seems likely since DNA damage repair is a complex process that involves several genes. Therefore we investigated if mutations in other genes are involved in cancer development and whether TNBC is an additional indicator of mutational status besides family history and age of onset. METHODS: We performed a germline panel-based screening of 10 high and low-moderate penetrance breast cancer susceptibility genes (BRCA1, BRCA2, ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D and TP53) in 229 consecutive individuals affected with TNBC unselected for age, family history or bilateral disease. Within this cohort we compared the number of mutation carriers fulfilling clinical selection criteria with the total number of carriers identified. RESULTS: Age at diagnosis ranged from 23 to 80 years with an average age of 50.2 years. In 57 women (24.9%) we detected a pathogenic mutation, with a higher frequency (29.7%) in the group manifesting cancer before 60 years. Deleterious BRCA1 mutations occurred in 14.8% of TNBC patients. These were predominantly recurrent frameshift mutations (24/34, 70.6%). Deleterious BRCA2 mutations occurred in 5.7% of patients, all but one (c.1813dupA) being unique. While no mutations were found in CDH1 and TP53, 10 mutations were detected in one of the six other predisposition genes. Remarkably, neither of the ATM, RAD51D, CHEK2 and PALB2 mutation carriers had a family history. Furthermore, patients with non-BRCA1/2 mutations were not significantly younger than mutation negative women (p = 0.3341). Most importantly, among the 57 mutation carriers, ten (17.5%) would be missed using current clinical testing criteria including five (8%) with BRCA1/2 mutations. CONCLUSIONS: In summary, our data confirm and expand previous studies of a high frequency of germline mutations in genes associated with ineffective repair of DNA damage in women with TNBCs. Neither age of onset, contralateral disease nor family history were able to discern all mutation positive individuals. Therefore, TNBC should be considered as an additional criterion for panel based genetic testing.


Assuntos
Análise Mutacional de DNA/métodos , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Seleção de Pacientes , Penetrância , Análise de Sequência de DNA , Adulto Jovem
14.
Geburtshilfe Frauenheilkd ; 78(5): 481-492, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29880983

RESUMO

Over the last two decades genetic testing for mutations in BRCA1 and BRCA2 has become standard of care for women and men who are at familial risk for breast or ovarian cancer. Currently, genetic testing more often also includes so-called panel genes, which are assumed to be moderate-risk genes for breast cancer. Recently, new large-scale studies provided more information about the risk estimation of those genes. The utilization of information on panel genes with regard to their association with the individual breast cancer risk might become part of future clinical practice. Furthermore, large efforts have been made to understand the influence of common genetic variants with a low impact on breast cancer risk. For this purpose, almost 450 000 individuals have been genotyped for almost 500 000 genetic variants in the OncoArray project. Based on first results it can be assumed that - together with previously identified common variants - more than 170 breast cancer risk single nucleotide polymorphisms can explain up to 18% of familial breast cancer risk. The knowledge about genetic and non-genetic risk factors and its implementation in clinical practice could especially be of use for individualized prevention. This includes an individualized risk prediction as well as the individualized selection of screening methods regarding imaging and possible lifestyle interventions. The aim of this review is to summarize the most recent developments in this area and to provide an overview on breast cancer risk genes, risk prediction models and their utilization for the individual patient.

15.
Breast Cancer Res Treat ; 171(1): 85-94, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29725888

RESUMO

PURPOSE: BRCA1/2 mutations influence the molecular characteristics and the effects of systemic treatment of breast cancer. This study investigates the impact of germline BRCA1/2 mutations on pathological complete response and prognosis in patients receiving neoadjuvant systemic chemotherapy. METHODS: Breast cancer patients were tested for a BRCA1/2 mutation in clinical routine work and were treated with anthracycline-based or platinum-based neoadjuvant chemotherapy between 1997 and 2015. These patients were identified in the tumor registry of the Breast Center of the University of Erlangen (Germany). Logistic regression and Cox regression analyses were performed to investigate the associations between BRCA1/2 mutation status, pathological complete response, disease-free survival, and overall survival. RESULTS: Among 355 patients, 59 had a mutation in BRCA1 or in BRCA2 (16.6%), 43 in BRCA1 (12.1%), and 16 in BRCA2 (4.5%). Pathological complete response defined as "ypT0; ypN0" was observed in 54.3% of BRCA1/2 mutation carriers, but only in 22.6% of non-carriers. The adjusted odds ratio was 2.48 (95% CI 1.26-4.91) for BRCA1/2 carriers versus non-carriers. Patients who achieved a pathological complete response had better disease-free survival and overall survival rates compared with those who did not achieve a pathological complete response, regardless of BRCA1/2 mutation status. CONCLUSIONS: BRCA1/2 mutation status leads to better responses to neoadjuvant chemotherapy in breast cancer. Pathological complete response is the main predictor of disease-free survival and overall survival, independently of BRCA1/2 mutation status.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Genes BRCA1 , Genes BRCA2 , Mutação , Adulto , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Terapia Combinada , Análise Mutacional de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Terapia Neoadjuvante , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Adulto Jovem
16.
Am J Hum Genet ; 102(3): 468-479, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29429572

RESUMO

Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Mutação/genética , Pescoço/anormalidades , Subunidades Proteicas/genética , Adolescente , Sequência de Aminoácidos , Animais , Células COS , Criança , Pré-Escolar , Proteínas de Ligação a DNA/química , Facies , Feminino , Células HEK293 , Histonas/metabolismo , Humanos , Masculino , Fenótipo
17.
Int J Cancer ; 140(1): 95-102, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27616075

RESUMO

Breast and ovarian cancer (BC/OC) predisposition has been attributed to a number of high- and moderate to low-penetrance susceptibility genes. With the advent of next generation sequencing (NGS) simultaneous testing of these genes has become feasible. In this monocentric study, we report results of panel-based screening of 14 BC/OC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, CHEK2, PALB2, ATM, NBN, CDH1, TP53, MLH1, MSH2, MSH6 and PMS2) in a group of 581 consecutive individuals from a German population with BC and/or OC fulfilling diagnostic criteria for BRCA1 and BRCA2 testing including 179 with a triple-negative tumor. Altogether we identified 106 deleterious mutations in 105 (18%) patients in 10 different genes, including seven different exon deletions. Of these 106 mutations, 16 (15%) were novel and only six were found in BRCA1/2. To further characterize mutations located in or nearby splicing consensus sites we performed RT-PCR analysis which allowed confirmation of pathogenicity in 7 of 9 mutations analyzed. In PALB2, we identified a deleterious variant in six cases. All but one were associated with early onset BC and a positive family history indicating that penetrance for PALB2 mutations is comparable to BRCA2. Overall, extended testing beyond BRCA1/2 identified a deleterious mutation in further 6% of patients. As a downside, 89 variants of uncertain significance were identified highlighting the need for comprehensive variant databases. In conclusion, panel testing yields more accurate information on genetic cancer risk than assessing BRCA1/2 alone and wide-spread testing will help improve penetrance assessment of variants in these risk genes.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Neoplasias Ovarianas/genética , Análise de Sequência de DNA/métodos , Idade de Início , Proteína BRCA1/genética , Proteína BRCA2 , Grupo com Ancestrais do Continente Europeu/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Alemanha , Humanos , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética
18.
J Neurol ; 263(11): 2308-2318, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27544505

RESUMO

Parkinson's disease (PD) is a progressive neurological disorder and appears to have gender-specific symptoms. Studies have observed a higher frequency for development of PD in male than in female. In the current study, we evaluated the gender-based changes in cortical thickness and structural connectivity in PD patients. With informed consent, 64 PD (43 males and 21 females) patients, and 46 (12 males and 34 females) age-matched controls underwent clinical assessment including Mini-Mental State Examination (MMSE) and magnetic resonance imaging on a 1.5 Tesla clinical MR scanner. Whole brain high-resolution T1-weighted images were acquired from all subjects and used to measure cortical thickness and structural network connectivity. No significant difference in MMSE score was observed between male and female both in control and PD subjects. Male PD patients showed significantly reduced cortical thickness in multiple brain regions including frontal, parietal, temporal, and occipital lobes as compared with those in female PD patients. The graph theory-based network analysis depicted lower connection strengths, lower clustering coefficients, and altered network hubs in PD male than in PD female. Male-specific cortical thickness changes and altered connectivity in PD patients may derive from behavioral, physiological, environmental, and genetical differences between male and female, and may have significant implications in diagnosing and treating PD among genders.


Assuntos
Córtex Cerebral/patologia , Vias Neurais/patologia , Doença de Parkinson/patologia , Caracteres Sexuais , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem
19.
Am J Hum Genet ; 97(3): 445-56, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26340334

RESUMO

The link of chromatin remodeling to both neurodevelopment and cancer has recently been highlighted by the identification of mutations affecting BAF chromatin-remodeling components, such as ARID1B, in individuals with intellectual disability and cancer. However, the underlying molecular mechanism(s) remains unknown. Here, we show that ARID1B is a repressor of Wnt/ß-catenin signaling. Through whole-transcriptome analysis, we find that in individuals with intellectual disability and ARID1B loss-of-function mutations, Wnt/ß-catenin target genes are upregulated. Using cellular models of low and high Wnt/ß-catenin activity, we demonstrate that knockdown of ARID1B activates Wnt/ß-catenin target genes and Wnt/ß-catenin-dependent transcriptional reporters in a ß-catenin-dependent manner. Reciprocally, forced expression of ARID1B inhibits Wnt/ß-catenin signaling downstream of the ß-catenin destruction complex. Both endogenous and exogenous ARID1B associate with ß-catenin and repress Wnt/ß-catenin-mediated transcription through the BAF core subunit BRG1. Accordingly, mutations in ARID1B leading to partial or complete deletion of its BRG1-binding domain, as is often observed in intellectual disability and cancers, compromise association with ß-catenin, and the resultant ARID1B mutant proteins fail to suppress Wnt/ß-catenin signaling. Finally, knockdown of ARID1B in mouse neuroblastoma cells leads to neurite outgrowth through ß-catenin. The data suggest that aberrations in chromatin-remodeling factors, such as ARID1B, might contribute to neurodevelopmental abnormalities and cancer through deregulation of developmental and oncogenic pathways, such as the Wnt/ß-catenin signaling pathway.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Via de Sinalização Wnt/genética , beta Catenina/metabolismo , Western Blotting , Biologia Computacional , DNA Complementar/biossíntese , Humanos , Imunoprecipitação , Luciferases , Microscopia de Fluorescência , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real
20.
Case Rep Urol ; 2013: 638125, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23956921

RESUMO

Duplication of the lower urinary tract is a very rare congenital anomaly which is diagnosed either at birth or during early childhood. These rare malformations are most of the times accompanied by other concomitant anomalies and are therefore diagnosed immediately after birth. In some even rarer cases there are no concomitant anomalies and symptoms thus leading to a diagnosis later in childhood. This is the first case in the literature of complete bladder duplication in the coronal plane with concomitant duplication of the urethra and no other associated anomalies in a 52-year-old male who remained asymptomatic and therefore undiagnosed for more than 5 decades.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA