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2.
Immunol Cell Biol ; 96(10): 1060-1071, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29790605

RESUMO

Premature T-cell immunosenescence with CD57+ CD8+ T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.

3.
J Clin Immunol ; 37(8): 770-780, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28936583

RESUMO

We report our experience in using flow cytometry-based immunological screening prospectively as a decision tool for the use of genetic studies in the diagnostic approach to patients with hemophagocytic lymphohistiocytosis (HLH). We restricted genetic analysis largely to patients with abnormal immunological screening, but included whole exome sequencing (WES) for those with normal findings upon Sanger sequencing. Among 290 children with suspected HLH analyzed between 2010 and 2014 (including 17 affected, but asymptomatic siblings), 87/162 patients with "full" HLH and 79/111 patients with "incomplete/atypical" HLH had normal immunological screening results. In 10 patients, degranulation could not be tested. Among the 166 patients with normal screening, genetic analysis was not performed in 107 (all with uneventful follow-up), while 154 single gene tests by Sanger sequencing in the remaining 59 patients only identified a single atypical CHS patient. Flow cytometry correctly predicted all 29 patients with FHL-2, XLP1 or 2. Among 85 patients with defective NK degranulation (including 13 asymptomatic siblings), 70 were Sanger sequenced resulting in a genetic diagnosis in 55 (79%). Eight patients underwent WES, revealing mutations in two known and one unknown cytotoxicity genes and one metabolic disease. FHL3 was the most frequent genetic diagnosis. Immunological screening provided an excellent decision tool for the need and depth of genetic analysis of HLH patients and provided functionally relevant information for rapid patient classification, contributing to a significant reduction in the time from diagnosis to transplantation in recent years.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Células Matadoras Naturais/imunologia , Proteínas com Domínio LIM/genética , Proteínas com Homeodomínio LIM/genética , Linfo-Histiocitose Hemofagocítica/diagnóstico , Proteínas Musculares/genética , Fatores de Transcrição/genética , Doenças Assintomáticas , Degranulação Celular , Criança , Citometria de Fluxo , Testes Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Proteínas com Homeodomínio LIM/metabolismo , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Proteínas Musculares/metabolismo , Mutação/genética , Transplante de Órgãos , Guias de Prática Clínica como Assunto , Prognóstico , Estudos Prospectivos , Irmãos , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Exoma
4.
Geburtshilfe Frauenheilkd ; 77(5): 516-523, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28579623

RESUMO

INTRODUCTION: Doppler sonography of the uterine artery (UA) is done to monitor pregnancies, because the detected flow patterns are useful to draw inferences about possible disorders of trophoblast invasion. Increased resistance in the UA is associated with an increased risk of preeclampsia and/or intrauterine growth restriction (IUGR) and perinatal mortality. In the absence of standardized figures, the normal ranges of the various available reference curves sometimes differ quite substantially from one another. The causes for this are differences in the flow patterns of the UA depending on the position of the pulsed Doppler gates as well as branching of the UA. Because of the discrepancies between the different reference curves and the practical problems this poses for guideline recommendations, we thought it would be useful to create our own reference curves for Doppler measurements of the UA obtained from a singleton cohort under standardized conditions. MATERIAL AND METHODS: This retrospective cohort study was carried out in the Department of Obstetrics of the Charité - Universitätsmedizin Berlin, the Department for Obstetrics and Prenatal Medicine of the University Hospital Halle (Saale) and the Center for Prenatal Diagnostics and Human Genetics Kurfürstendamm 199. Available datasets from the three study locations were identified and reference curves were generated using the LMS method. Measured values were correlated with age of gestation, and a cubic model and Box-Cox power transformation (L), the median (M) and the coefficient of variation (S) were used to smooth the curves. RESULTS: 103 720 Doppler examinations of the UA carried out in singleton pregnancies from the 11th week of gestation (10 + 1 GW) were analyzed. The mean pulsatility index (Mean PI) showed a continuous decline over the course of pregnancy, dropping to a plateau of around 0.84 between the 23rd and 27th GW, after which it decreased again. CONCLUSION: Age of gestation, placental position, position of pulsed Doppler gates and branching of the UA can all change the flow pattern. The mean pulsatility index (Mean PI) showed a continuous decrease over time. There were significant differences between our data and alternative reference curves. A system of classifying Doppler studies and a reference curve adapted to the current technology are urgently required to differentiate better between physiological and pathological findings.

5.
Haematologica ; 102(2): e52-e56, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27789675
6.
Eur J Immunol ; 47(2): 364-373, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27925643

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome characterized by hyperactivation of lymphocytes and histiocytes. T cells play a key role in HLH pathogenesis, but their differentiation pattern is not well characterized in patients with active HLH. We compared T-cell activation patterns between patients with familial HLH (1°HLH), 2°HLH without apparent infectious trigger (2°HLH) and 2°HLH induced by a viral infection (2°V-HLH). Polyclonal CD8+ T cells are highly activated in 1°HLH and 2°V-HLH, but less in 2°HLH as assessed by HLA-DR expression and marker combination with CD45RA, CCR7, CD127, PD-1 and CD57. Absence of increased HLA-DR expression on T cells excluded active 1° HLH with high sensitivity and specificity. A high proportion of polyclonal CD127- CD4+ T cells expressing HLA-DR, CD57, and perforin is a signature of infants with 1°HLH, much less prominent in virus-associated 2°HLH. The similar pattern and extent of CD8+ T-cell activation compared to 2° V-HLH is compatible with a viral trigger of 1°HLH. However, in most 1°HLH patients no triggering infection was documented and the unique activation of cytotoxic CD4+ T cells indicates that the overall T-cell response in 1°HLH is different. This may reflect different pathways of pathogenesis of these two HLH variants.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Viroses/imunologia , Antígenos CD57/metabolismo , Diferenciação Celular , Células Cultivadas , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Lactente , Recém-Nascido , Ativação Linfocitária , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Masculino , Perforina/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Viroses/complicações , Viroses/diagnóstico
7.
Blood ; 128(2): 227-38, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27099149

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαß(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/imunologia , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lectinas Tipo C/imunologia , Antígenos Comuns de Leucócito/imunologia , Masculino , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transativadores/imunologia
9.
J Allergy Clin Immunol ; 136(2): 392-401, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25702838

RESUMO

BACKGROUND: Most patients with MHC class I (MHC-I) deficiency carry genetic defects in transporter associated with antigen processing 1 (TAP1) or TAP2. The clinical presentation can vary, and about half of the patients have severe skin disease. Previously, one report described ß2-microglobulin (ß2m) deficiency as another monogenetic cause of MHC-I deficiency, but no further immunologic evaluation was performed. OBJECTIVE: We sought to describe the molecular and immunologic features of ß2m deficiency in 2 Turkish siblings with new diagnoses. METHODS: Based on clinical and serologic findings, the genetic defect was detected by means of candidate gene analysis. The immunologic characterization comprises flow cytometry, ELISA, functional assays, and immunohistochemistry. RESULTS: Here we provide the first extensive clinical and immunologic description of ß2m deficiency in 2 siblings. The sister had recurrent respiratory tract infections and severe skin disease, whereas the brother was fairly asymptomatic but had bronchiectasis. Not only polymorphic MHC-I but also the related CD1a, CD1b, CD1c, and neonatal Fc receptor molecules were absent from the surfaces of ß2m-deficient cells. Absent neonatal Fc receptor surface expression led to low serum IgG and albumin levels in both siblings, whereas the heterozygous parents had normal results for all tested parameters except ß2m mRNA (B2M) expression. Similar to TAP deficiency in the absence of a regular CD8 T-cell compartment, CD8(+) γδ T cells were strongly expanded. Natural killer cells were normal in number but not "licensed to kill." CONCLUSION: The clinical presentation of patients with ß2m deficiency resembles that of patients with other forms of MHC-I deficiency, but because of the missing stabilizing effect of ß2m on other members of the MHC-I family, the immunologic defect is more extensive than in patients with TAP deficiency.


Assuntos
Bronquiectasia/imunologia , Síndromes de Imunodeficiência/imunologia , Infecções Respiratórias/imunologia , Úlcera Cutânea/imunologia , Microglobulina beta-2/imunologia , Imunidade Adaptativa , Adolescente , Adulto , Antígenos CD1/genética , Antígenos CD1/imunologia , Bronquiectasia/complicações , Bronquiectasia/genética , Bronquiectasia/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Consanguinidade , Feminino , Deleção de Genes , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata , Imunoglobulina G/sangue , Imunoglobulina G/genética , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Linhagem , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Receptores Fc/deficiência , Receptores Fc/genética , Receptores Fc/imunologia , Recidiva , Infecções Respiratórias/complicações , Infecções Respiratórias/genética , Infecções Respiratórias/patologia , Irmãos , Úlcera Cutânea/complicações , Úlcera Cutânea/genética , Úlcera Cutânea/patologia , Microglobulina beta-2/deficiência , Microglobulina beta-2/genética
10.
J Clin Immunol ; 35(1): 22-5, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25491289

RESUMO

Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous hyperinflammatory syndrome, caused by an uncontrolled and ineffective proliferation and activation of T-lymphocytes, NK-cells, and macrophages that infiltrate multiple organs. Herein, a patient is presented who suffered from hepatitis and atypical brain lesions. Genetic studies revealed a homozygous mutation in the STXP2 gene; and thus, the diagnosis of FHL5 was confirmed.


Assuntos
Linfo-Histiocitose Hemofagocítica/genética , Proteínas Munc18/genética , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Idade de Início , Encéfalo/patologia , Criança , Evolução Fatal , Hepatite Autoimune/genética , Hepatite Autoimune/imunologia , Homozigoto , Humanos , Células Matadoras Naturais/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/imunologia , Imagem por Ressonância Magnética , Masculino , Mutação , Linfócitos T/imunologia
11.
Eur J Immunol ; 44(10): 3129-40, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25042067

RESUMO

X-linked severe combined immunodeficiency (X-SCID) leads to a T(-) NK(-) B(+) immunophenotype and is caused by mutations in the gene encoding the IL-2 receptor γ-chain (IL2RG). IL2RG(R222C) leads to atypical SCID with a severe early onset phenotype despite largely normal NK- and T-cell numbers. To address this discrepancy, we performed a detailed analysis of T, B, and NK cells, including quantitative STAT phosphorylation and functional responses to the cytokines IL-2, IL-4, IL-15, and IL-21 in a patient with the IL2RG(R222C) mutation. Moreover, we identified nine additional unpublished patients with the same mutations, all with a full SCID phenotype, and confirmed selected immunological observations. T-cell development was variably affected, but led to borderline T-cell receptor excision circle (TREC) levels and a normal repertoire. T cells showed moderately reduced proliferation, failing enhancement by IL-2. While NK-cell development was normal, IL-2 enhancement of NK-cell degranulation and IL-15-induced cytokine production were absent. IL-2 or IL-21 failed to enhance B-cell proliferation and plasmablast differentiation. These functional alterations were reflected by a differential impact of IL2RG(R222C) on cytokine signal transduction, with a gradient IL-4

Assuntos
Linfócitos B/imunologia , Citocinas/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Células Matadoras Naturais/imunologia , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Humanos , Lactente , Subunidade gama Comum de Receptores de Interleucina/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Mutação , Fenótipo , Transdução de Sinais/imunologia
12.
Blood ; 124(6): 851-60, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-24894771

RESUMO

Accumulation of CD3(+) T-cell receptor (TCR)αß(+)CD4(-)CD8(-) double-negative T cells (DNT) is a hallmark of autoimmune lymphoproliferative syndrome (ALPS). DNT origin and differentiation pathways remain controversial. Here we show that human ALPS DNT have features of terminally differentiated effector memory T cells reexpressing CD45RA(+) (TEMRA), but are CD27(+)CD28(+)KLRG1(-) and do not express the transcription factor T-bet. This unique phenotype was also detected among CD4(+) or CD8(+) ALPS TEMRA cells. T-cell receptor ß deep sequencing revealed a significant fraction of shared CDR3 sequences between ALPS DNT and both CD4(+) and CD8(+)TEMRA cells. Moreover, in ALPS patients with a germ line FAS mutation and somatic loss of heterozygosity, in whom biallelic mutant cells can be tracked by absent Fas expression, Fas-negative T cells accumulated not only among DNT, but also among CD4(+) and CD8(+)TEMRA cells. These data indicate that in human Fas deficiency DNT cannot only derive from CD8(+), but also from CD4(+) T cells. Furthermore, defective Fas signaling leads to aberrant transcriptional programs and differentiation of subsets of CD4(+) and CD8(+) T cells. Accumulation of these cells before their double-negative state appears to be an important early event in the pathogenesis of lymphoproliferation in ALPS patients.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Receptor fas/deficiência , Receptor fas/genética , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/genética , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Criança , Pré-Escolar , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Humanos , Memória Imunológica , Antígenos Comuns de Leucócito/metabolismo , Perda de Heterozigosidade , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
13.
Haematologica ; 98(12): 1948-55, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23850805

RESUMO

Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3(+)TCRα/ß(+)CD4(-)CD8(-) "double negative" T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.


Assuntos
Proteína Ligante Fas/sangue , Proteína Ligante Fas/genética , Transtornos Linfoproliferativos/sangue , Transtornos Linfoproliferativos/genética , Vitamina B 12/sangue , Adolescente , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Transtornos Linfoproliferativos/diagnóstico , Masculino
14.
J Allergy Clin Immunol ; 131(2): 477-85.e1, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23374270

RESUMO

BACKGROUND: Profound combined immunodeficiency can present with normal numbers of T and B cells, and therefore the functional defect of the cellular and humoral immune response is often not recognized until the first severe clinical manifestation. Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history. OBJECTIVE: We sought to identify the genetic alteration in a patient with combined immunodeficiency and characterize human caspase recruitment domain family, member 11 (CARD11), deficiency. METHODS: Molecular, immunologic, and functional assays were performed. RESULTS: The immunologic characterization revealed only subtle changes in the T-cell and natural killer cell compartment, whereas B-cell differentiation, although normal in number, was distinctively blocked at the transitional stage. Genetic evaluation revealed a homozygous deletion of exon 21 in CARD11 as the underlying defect. This deletion abrogated protein expression and activation of the canonical nuclear factor κB (NF-κB) pathway in lymphocytes after antigen receptor or phorbol 12-myristate 13-acetate stimulation, whereas CD40 signaling in B cells was preserved. The abrogated activation of the canonical NF-κB pathway was associated with severely impaired upregulation of inducible T-cell costimulator, OX40, cytokine production, proliferation of T cells, and B cell-activating factor receptor expression on B cells. CONCLUSION: Thus in patients with CARD11 deficiency, the combination of impaired activation and especially upregulation of inducible T-cell costimulator on T cells, together with severely disturbed peripheral B-cell differentiation, apparently leads to a defective T-cell/B-cell cooperation and probably germinal center formation and clinically results in severe immunodeficiency. This report discloses the crucial and nonredundant role of canonical NF-κB activation and specifically CARD11 in the antigen-specific immune response in human subjects.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/deficiência , Guanilato Ciclase/deficiência , Síndromes de Imunodeficiência/enzimologia , Deleção de Sequência , Agamaglobulinemia/enzimologia , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Feminino , Guanilato Ciclase/genética , Guanilato Ciclase/imunologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Lactente
16.
Fetal Diagn Ther ; 27(4): 191-203, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20357423

RESUMO

INTRODUCTION: Mirror syndrome, also referred to as Ballantyne's syndrome, is normally defined as the development of maternal edema in association with fetal hydrops. The incidence of mirror syndrome is low and few cases have been published. We describe a case report in association with fetal Ebstein anomaly and provide a systematic review on the fetal associated conditions, maternal presentation and perinatal outcome reported for mirror syndrome. DATA SOURCES: A PubMed database search was done until December 2008 (English, French or German) without any restriction of publication date or journal, using the following key words: Ballantyne syndrome, Mirror syndrome, Triple edema, Pseudotoxemia, Maternal hydrops syndrome, Pregnancy toxemia, Acute second trimester gestosis, and Early onset preeclampsia. Reported cases were considered eligible when fetal associated conditions, maternal symptoms and fetal outcome were clearly described. RESULTS: Among 151 publications a total of 56 reported cases satisfying all inclusion criteria were identified. Mirror syndrome was associated with rhesus isoimmunization (29%), twin-twin transfusion syndrome (18%), viral infection (16%) and fetal malformations, fetal or placental tumors (37.5%). Gestational age at diagnosis ranged from 22.5 to 27.8 weeks of gestation. Maternal key signs were edema (80-100%), hypertension (57-78%) and proteinuria (20-56%). The overall rate of intrauterine death was 56%. Severe maternal complications including pulmonary edema occurred in 21.4%. Maternal symptoms disappeared 4.8-13.5 days after delivery. DISCUSSION: Mirror syndrome is associated with a substantial increase in fetal mortality and maternal morbidity.


Assuntos
Anomalia de Ebstein/diagnóstico , Edema/diagnóstico , Hidropisia Fetal/diagnóstico , Complicações na Gravidez/diagnóstico , Adulto , Anomalia de Ebstein/complicações , Anomalia de Ebstein/patologia , Edema/sangue , Edema/etiologia , Feminino , Humanos , Hidropisia Fetal/patologia , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/terapia , Resultado da Gravidez , Isoimunização Rh/complicações , Síndrome
17.
Anticancer Res ; 29(2): 641-5, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19331214

RESUMO

AIM: To study the impact of circulating vascular endothelial growth factors (VEGF) -A, -C and -D and their soluble receptors VEGFR-1/-2 on disease invasion and progression in patients with pre-invasive (CIN), invasive (PCC) and recurrent (RCC) cervical cancer. PATIENTS AND METHODS: Blood samples were obtained from 125 women, including 50 cases of CIN, 51 of PCC and 24 of RCC, before treatment. Soluble (s) biomarker levels were determined by ELISA and tested for correlation with histopathological factors. RESULTS: With disease progression, sVEGF-A (p = 0.007) and sVEGFR-2 (p = 0.014) significantly increased, while sVEGF-D (p = 0.046) decreased. sVEGFR-2 levels were increased in node+ patients (p = 0.024) and in metastatic disease (p = 0.003). sVEGF-A values were higher in HPV+ cases (p = 0.019). In detecting disease invasiveness, sensitivity and specificity were 76% and 48% for sVEGF-A, 52% and 32% for sVEGF-D, 25% and 94% for sVEGF-C, 93% and 6% for sVEGFR-1 and 73% and 34% for sVEGFR-2, respectively. CONCLUSION: In cervical neoplasia, a switch from a lymphangiogenic phenotype towards a hemangiogenic phenotype occurs with disease invasion and progression. The sensitivity and specificity values, however, seem not convincing enough to establish these factors as clinical markers for disease invasiveness in cervical cancer.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasia Intraepitelial Cervical/sangue , Recidiva Local de Neoplasia/sangue , Neoplasias do Colo do Útero/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Neoplasia Intraepitelial Cervical/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias do Colo do Útero/patologia
18.
J Clin Oncol ; 25(22): 3246-50, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17577021

RESUMO

PURPOSE: The oral fluoropyrimidine carbamate, capecitabine, is a highly active and well-tolerated treatment for metastatic breast cancer. In patients treated previously with anthracyclines and taxanes, capecitabine is an approved single-agent therapy. Trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER-2), is also highly active in HER-2-overexpressing breast cancer. We have conducted a phase II study to confirm activity and feasibility of capecitabine and trastuzumab in combination in HER-2-overexpressing advanced/metastatic breast cancer. PATIENTS AND METHODS: Twenty-seven patients with HER-2-overexpressing metastatic breast cancer previously treated with anthracyclines and/or taxanes received oral capecitabine 1,250 mg/m(2) bid for 14 days followed by a 7-day rest period combined with intravenous trastuzumab 4 mg/kg body weight on day 1 (loading dose) followed by 2 mg/kg weekly. RESULTS: Capecitabine/trastuzumab treatment achieved objective responses in 12 patients (45%), including complete response in four patients (15%) and partial response in eight patients (30%). Disease was stabilized in an additional nine patients (33%). The median overall survival time was 28 months, and the median progression-free survival time was 6.7 months. The safety profile of the combination was favorable and predictable, with a low incidence of grade 3/4 adverse events. The most common adverse events were pain, hand-foot syndrome, and GI toxicities. Severe myelosuppression was rare and severe alopecia did not occur. CONCLUSION: These data confirm that the combination of capecitabine and trastuzumab is highly active in patients with HER-2-overexpressing anthracycline- and/or taxane-pretreated breast cancer, with only slight restrictions regarding quality of life.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Receptores ErbB/antagonistas & inibidores , Fluoruracila/análogos & derivados , Adulto , Idoso , Antraciclinas/administração & dosagem , Anticorpos Monoclonais Humanizados , Antimetabólitos Antineoplásicos/administração & dosagem , Capecitabina , Desoxicitidina/administração & dosagem , Progressão da Doença , Fluoruracila/administração & dosagem , Alemanha , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/análise , Taxa de Sobrevida , Taxoides/administração & dosagem , Trastuzumab , Resultado do Tratamento
19.
Anticancer Res ; 27(6C): 4289-94, 2007 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18214033

RESUMO

BACKGROUND: This prospective study evaluates the predictive value of preoperative staging by transvaginal sonography (TVS) in ovarian cancer. PATIENTS AND METHODS: In 39 patients presenting with clinical signs and symptoms of ovarian cancer, preoperative systematic staging regarding tumor size (T), presence of ascites (A), peritoneal carcinomatosis (PC), bladder invasion (BI), intestinal invasion (II) as well as pelvic lymph node involvement (LN), were evaluated by TVS. Findings combining conventional B-mode ultrasound and Color Doppler imaging were compared to preoperative findings and final histology results. RESULTS: Preoperative staging was correctly achieved by TVS for T in 87%, for A in 97% (95% CI: 90-100), for PC in 96% (95% CI: 86-100), for BI in 99% (95% CI: 95-100), for II in 98% (95% CI: 93-100). The predictive value of TVS for LN was minor (sensitivity: 8%, 95% CI: 7-24). CONCLUSION: TVS is a sensitive and noninvasive method for preoperative staging of suspected ovarian cancer regarding tumor size, ascites, invasion of adjacent organs and peritoneal carcinomatosis, but not for detection of malignant lymph nodes. The need for invasive or more elaborate diagnostic tools such as CT and MRI, cystoscopy, rectoscopy and diagnostic ascites punction can potentially be reduced by systematic use of TVS.


Assuntos
Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Cuidados Pré-Operatórios , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico por imagem , Metástase Neoplásica/patologia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Prospectivos , Ultrassonografia Doppler em Cores
20.
Anticancer Res ; 26(6B): 4397-401, 2006 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17201160

RESUMO

BACKGROUND: Since the anti-HER2 monoclonal antibody trastuzumab made its triumphant advance into breast cancer therapy, new selective agents, including pan-HER inhibitors are entering clinical practice. MATERIALS AND METHODS: This study investigates the expression of the four HER-family members, HER1-4, in 48 primary breast carcinomas (PBC) and corresponding distant metastases (CDM) by immunohistochemistry and fluorescence in situ hybridisation. RESULTS: Concordance rate between PBC and CDM was 79% for HERI and HER2, 67% for HER3 and 56% or HER4. Expression of HER1-3 was associated with poor prognosis compared to HER-negative disease (p = 0.036). HER4 overexpression was associated with a better outcome (p = 0.003). CONCLUSION: Though most tumours demonstrate a stable HER expression pattern, both loss and acquisition of HER receptor overexpression can occur during metastasis. HER4 overexpression predicts prolonged survival compared to receptor negative disease, while the opposite is true for HER1-3. Consequences for modem antibody therapy are discussed.


Assuntos
Neoplasias da Mama/metabolismo , Receptores ErbB/metabolismo , Metástase Neoplásica , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Prognóstico
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