RESUMO
OBJECTIVE: Despite its generally favorable prognosis at primary diagnosis, recurrence of endometrial cancer remains an important clinical challenge. The aim of this study was to analyze the value of molecular classification in recurrent endometrial cancer. METHODS: This study included patients with recurrent endometrial cancer who underwent primary surgical treatment between 2004 and 2015 at the Karolinska University Hospital, Sweden and the Bern University Hospital, Switzerland (KImBer cohort) with molecular classification of the primary tumor. RESULTS: Out of 594 molecularly classified endometrial cancer patients, 101 patients experienced recurrence, consisting of 2 POLEmut, 33 MMRd, 30 p53abn, and 36 NSMP tumors. Mean age at recurrence was 71 years and mean follow-up was 54 months. Overall, median time to first recurrence was 16 months (95% CI 12-20); with the shortest median time in MMRd patients, with 13 months (95% CI 5-21). The pattern of recurrence was distinct among molecular subgroups: MMRd tumors experienced more locoregional, while p53abn cases showed more abdominal recurrences (P = .042). Median survival after recurrence was best for MMRd cases (43 months, 95% CI 11-76), compared to 39 months (95% CI 21-57) and 10 months (95% CI 7-13) for the NSMP and p53abn cases respectively (log-rank, P = .001). CONCLUSION: Molecular classification is a significant indicator of survival after recurrence in endometrial cancer patients, and patterns of recurrence differ by molecular subgroups. While MMRd endometrial cancer show more locoregional recurrence and the best survival rates after recurrence, p53abn patients experience abdominal recurrence more often and had the worst prognosis of all recurrent patients.
Assuntos
Neoplasias do Endométrio , Proteína Supressora de Tumor p53 , Estudos de Coortes , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genéticaRESUMO
The pathologist can contribute to recognizing hereditary causes of colorectal cancer via morphology. By identifying so-called index patients, it is possible to take preventive measures in affected families. The precise definition of the clinical presentation and the histopathological phenotype help to narrow the spectrum of expected genetic alterations. Novelties within Lynch syndrome include the recognition of EPCAM as a fifth gene locus, as well as the newly defined Lynch-like syndrome with evidence of somatic mismatch repair (MMR) mutations. With regard to polyposis-associated syndromes, the spectrum of polyps, whether serrated, hamartomatous or classic adenoma, is of crucial importance. The resulting differential diagnosis includes (attenuated) familial adenomatous polyposis ([a]FAP), MUTYH-associated polyposis (MAP), polymerase proofreading-associated polyposis (PPAP), phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS), Peutz-Jeghers syndrome and juvenile polyposis, each with a specific genetic background.
Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Colorretais Hereditárias sem Polipose , Diagnóstico Diferencial , Humanos , Síndrome de Peutz-JeghersRESUMO
The fifth "Melanoma Bridge Meeting" took place in Naples, December 1-5th, 2015. The main topics discussed at this meeting were: Molecular and Immuno advances, Immunotherapies and Combination Therapies, Tumor Microenvironment and Biomarkers and Immunoscore. The natural history of cancer involves interactions between the tumor and the immune system of the host. The immune infiltration at the tumor site may be indicative of host response. Significant correlations were shown between the levels of immune cell infiltration in tumors and patient's clinical outcome. Moreover, incredible progress comes from the discovery of mutation-encoded tumor neoantigens. In fact, as tumors grow, they acquire mutations that are able to influence the response of patients to immune checkpoint inhibitors. It has been demonstrated that sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. The road ahead is still very long, but the knowledge of the mechanisms of immune escape, the study of tumor neo-antigens as well as of tumor microenvironment and the development of new immunotherapy strategies, will make cancer a more and more treatable disease.
Assuntos
Imunoterapia , Melanoma/imunologia , HumanosRESUMO
The pathogenesis of precursor lesions of gastrointestinal tumors is manifested in many ways. In the esophagus an aberrant genetic expression of intestinal transcription factors, such as CDX2 is initiated by local environment factors. During the subsequent dysplasia to carcinoma sequence, chromosomal gain and loss of genes occurs. A 4-color fluorescence in situ hybridization (FISH) assay can be applied in dysplasia as well as in Barrett's adenocarcinoma to define prognostic marker combinations. In the gastric carcinogenesis sequence the gene expression of CDX1 is regulatively dependent on an interplay between inflammation and promotor methylation. In the colon sessile serrated adenomas show a sequence with initial BRAF mutation and late onset of MLH1 promotor hypermethylation with consecutive potential cancer progression. This event is accompanied by an increase of intraepithelial lymphocytes, which is an easy to use tool for routine diagnostics using H&E sections. Next generation sequencing (NGS) investigations of germline mutations in colorectal cancer revealed a spectrum of mutations with low penetration in the field of mismatch repair proteins as well as the APC gene. An individual risk stratification for penetration of these germline mutations is necessary. In conclusion, genetics, phenotypes and terminology of gastrointestinal precursor lesions are unified to a mutually influencing concept within medicine.
Assuntos
Neoplasias Gastrointestinais/patologia , Lesões Pré-Cancerosas/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA/genética , Progressão da Doença , Neoplasias Gastrointestinais/genética , Regulação Neoplásica da Expressão Gênica/genética , Mutação em Linhagem Germinativa/genética , Humanos , Hibridização in Situ Fluorescente , Metilação , Fenótipo , Lesões Pré-Cancerosas/genética , Regiões Promotoras Genéticas/genéticaRESUMO
BACKGROUND: Oesophageal adenocarcinoma or Barrett's adenocarcinoma (EAC) is increasing in incidence and stratification of prognosis might improve disease management. Multi-colour fluorescence in situ hybridisation (FISH) investigating ERBB2, MYC, CDKN2A and ZNF217 has recently shown promising results for the diagnosis of dysplasia and cancer using cytological samples. METHODS: To identify markers of prognosis we targeted four selected gene loci using multi-colour FISH applied to a tissue microarray containing 130 EAC samples. Prognostic predictors (P1, P2, P3) based on genomic copy numbers of the four loci were statistically assessed to stratify patients according to overall survival in combination with clinical data. RESULTS: The best stratification into favourable and unfavourable prognoses was shown by P1, percentage of cells with less than two ZNF217 signals; P2, percentage of cells with fewer ERBB2- than ZNF217 signals; and P3, overall ratio of ERBB2-/ZNF217 signals. Median survival times for P1 were 32 vs 73 months, 28 vs 73 months for P2; and 27 vs 65 months for P3. Regarding each tumour grade P2 subdivided patients into distinct prognostic groups independently within each grade, with different median survival times of at least 35 months. CONCLUSIONS: Cell signal number of the ERBB2 and ZNF217 loci showed independence from tumour stage and differentiation grade. The prognostic value of multi-colour FISH-assays is applicable to EAC and is superior to single markers.
Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Biomarcadores Tumorais/genética , Neoplasias Esofágicas/patologia , Hibridização in Situ Fluorescente/métodos , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , DNA de Neoplasias/genética , Neoplasias Esofágicas/mortalidade , Feminino , Dosagem de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas c-myc/genética , Receptor ErbB-2/genética , Transativadores/genéticaRESUMO
BACKGROUND: Besides the conventional clear-cell renal cell carcinoma (ccRCC), papillary RCC (pRCC) is the second most common renal malignancy. Papillary RCCs can further be subdivided into two distinct subtypes. Although a clinical relevance of pRCC subtyping has been shown, little is known about the molecular characteristics of both pRCC subtypes. METHODS: We performed microarray-based microRNA (miRNA) expression profiling of primary ccRCC and pRCC cases. A subset of miRNAs was identified and used to establish a classification model for ccRCC, pRCC types 1 and 2 and normal tissue. Furthermore, we performed gene set enrichment analysis with the predicted miRNA target genes. RESULTS: Only five miRNAs (miR-145, -200c, -210, -502-3p and let-7c) were sufficient to identify the samples with high accuracy. In a collection of 111 tissue samples, 73.9% were classified correctly. An enrichment of miRNA target genes in the family of multidrug-resistance proteins was noted in all tumours. Several components of the Jak-STAT signalling pathway might be targets for miRNAs that define pRCC tumour subtypes. CONCLUSION: MicroRNAs are able to accurately classify RCC samples. Deregulated miRNAs might contribute to the high chemotherapy resistance of RCC. Furthermore, our results indicate that pRCC type 2 tumours could be dependent on oncogenic MYC signalling.
Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , MicroRNAs/genética , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/patologia , Estudos de Coortes , Perfilação da Expressão Gênica , Humanos , Neoplasias Renais/classificação , Neoplasias Renais/patologia , MicroRNAs/biossíntese , Análise de Componente PrincipalRESUMO
PURPOSE: To analyse multiparametric magnetic resonance imaging (mpMRI) characteristics and appearance of histopathologically proven non-cancerous intraprostatic findings focussing on quantity of prostatitis and atrophy in the peripheral zone. METHOD: In this retrospective analysis consecutive patients with mpMRI followed by MRI/TRUS-fusion biopsy comprising targeted (TB) and systematic biopsy (SB) cores without prostate cancer (PC) at histopathology were included. Subgroup analysis was performed in younger men (≤50 years). The proportions of prostatitis and atrophy were quantified for each biopsy core based on histopathology. MRI findings in the peripheral zone (PZ) and index lesions (IL, most suspicious/representative lesion) were characterized regarding changes in T2w, ADC value, and enhancement of dynamic contrast enhancement (DCE) and correlated with quantity of prostatitis and atrophy. RESULTS: Seventy-two patients were analysed. The median baseline characteristics were PSA 5.4 ng/ml (4.0-7.9), PI-RADS classification 3 (2-4), prostate volume 43 ml (33-57), and PSA density 0.13 ng/ml2 (0.10-0.19). Prostatitis was found in 44 % (n = 32) and atrophy in 65 % (n = 47) of cases. The quantity of atrophy demonstrated a significant correlation to T2w changes, ADC increase and DCE enhancement (p = 0.05, p = 0.05, p = 0.01), whereas quantity of prostatitis did not show any significant correlation to the MRI changes (p = 0.68, p = 0.58, p = 0.95). Quantity of prostatitis and atrophy increased with PI-RADS classification. Younger men had lower PSA (4.4 vs. 7.8 ml/ng; p < 0.001), smaller prostate volume (40 vs. 59 ml; p = 0.001), and lower PI-RADS classification (2-3 vs. 3-4; p = 0.005) and prostatitis and atrophy were less frequently observed (p ≤ 0.01, p = 0.03). CONCLUSIONS: Quantity of atrophy and prostatitis had different influence on MRI characteristics and increased within higher PI-RADS classification. Younger men had diffuse hypointense changes at T2w images, but less quantity of prostatitis and atrophy.
Assuntos
Imageamento por Ressonância Magnética Multiparamétrica , Neoplasias da Próstata , Prostatite , Masculino , Humanos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Imageamento por Ressonância Magnética/métodos , Prostatite/diagnóstico por imagem , Antígeno Prostático Específico , Estudos Retrospectivos , Biópsia Guiada por Imagem/métodosRESUMO
BACKGROUND: TACE/ADAM17 is a transmembranous protease that cleaves membrane-bound growth factors like EGFR ligands. TACE-dependent proteolysis is regulated by its inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP3). This study analyses the role of TACE and TIMP3 mRNA expression in squamous cell carcinomas of the head and neck (HNSCCs). METHODS: We analysed TACE and TIMP3 mRNA expression in HNSCCs from 106 patients by RNA in situ hybridisation. RESULTS: TACE mRNA was upregulated in HNSCCs compared with dysplastic (P<0.05) and normal epithelia (P<0.001), with strong hybridisation signals in 21.9% of invasive tumour tissues and 4.5% of dysplasia. Elevated mRNA levels were accompanied by increased amounts of TACE protein in HNSCCs. TIMP3 mRNA expression in HNSCC-associated stroma was significantly higher than in the stroma adjacent to dysplastic or normal epithelia. Expression of TACE mRNA in HNSCCs was associated with tumour stage (P=0.019) and regional lymph node metastasis (P=0.009). Furthermore, levels of TACE mRNA in HNSCCs correlated with the expression of TIMP3 mRNA in HNSCC-associated stroma. Concomitantly, patients expressing high levels of TACE and TIMP3 mRNA showed significantly reduced overall survival compared with those with low mRNA levels. CONCLUSION: Our results indicate an important role of TACE and TIMP3 during development and progression of HNSCCs.
Assuntos
Proteínas ADAM/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , RNA Mensageiro/genética , Inibidor Tecidual de Metaloproteinase-3/genética , Proteínas ADAM/metabolismo , Proteína ADAM17 , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma de Células Escamosas , Progressão da Doença , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Técnicas Imunoenzimáticas , Hibridização In Situ , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias de Células Escamosas/genética , Neoplasias de Células Escamosas/metabolismo , Neoplasias de Células Escamosas/patologia , Prognóstico , Sondas RNA , RNA Mensageiro/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxa de Sobrevida , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Células Tumorais CultivadasRESUMO
BACKGROUND: The department of ophthalmology at the medical faculty of the University of Ulm provides additionally for interested students in clinical semesters an optional activity. In small groups the students deepen their theoretical knowledge and learn more about ophthalmological diagnostic standard procedures. The "objective structured clinical examination" (OSCE) is known as a useful tool in the assessment of clinical skills. The OSCE is a well-established and valid examination method, but also time-consuming and costly. In form of a trial the OSCE was launched during the optional activity "Look into my eyes, baby"; in the summer semester 2009. METHODS: By means of four examination areas established diagnostic methods in ophthalmology were tested. During the tests two simulation patients as well as two phantom heads for ophthalmological examinations were assessed. The preparation of the examination materials occurred in close collaboration with the department of ophthalmology and the division exam development of our university. In the assessment of the examinations a high value was set on good communication skills between students and simulation patients as well as on the professional handling of the student tasks. After the examinations the acceptance of the test methods was evaluated using a focused group interview between the students of the optional activity and the participating examiners. RESULTS: We performed two OSCEs involving three students each in the last two semesters. The OSCE was to a great extent time- and resource-consuming, due to the intensive pre- and post-reviewing and the time students needed to pass the various examination areas. Students and examiners as well confirmed the validity of the assessment and acknowledged a positive effect on the students learning behaviour. CONCLUSIONS: The teaching staff members are willing to accept the OSCE, especially when the assessment procedures are thoroughly planned and well structured. The acceptance of the students can be achieved by providing valid assessment and reviewed teaching conditions. The high input in personnel and instrumental resources for the assessment and the student's individual supervision should be critically discussed in the light of the efficacy of the additional ongoing hospital and outpatient services and the personnel-relevant education budget assigned to the department of ophthalmology of a university.
Assuntos
Atitude do Pessoal de Saúde , Avaliação Educacional/métodos , Internato e Residência , Oftalmologia/educação , Currículo , AlemanhaRESUMO
One third of colorectal carcinomas (CRC) show familial clustering of which about 5% have a monogenetic trait. Distinction between disease with and without polyposis, tumor histology and tumor spectrum in a given patient are all of diagnostic relevance. Familial adenomatous polyposis (FAP) underlies approximately 1% of CRC characterized by rapidly forming (>100) adenomas. In contrast to these about 2%-3% of CRC have a hereditary background without polyposis (HNPCC). This is the only hereditary tumour syndrome to date for which a tissue-based molecular screening test is available. Accordingly, expression analysis of mismatch repair genes (MSH2, MSH6 and MLH1, PMS2) is performed first. In the case of an equivocal result with no complete loss of expression testing of microsatellite instability (MSI) is added. In contrast to the other diseases MYH-associated polyposis (MAP) follows a recessive trait with polyp numbers usually between 15-30 adenomas and should be distinguished from attenuated forms of FAP with <100 polyps in the differential diagnosis. In the case of suspected familial cancer syndrome genetic counseling is warranted in order to decide ultimately whether there is an indication for genetic testing (evidence of a germ-line mutation).
Assuntos
Polipose Adenomatosa do Colo/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Adenoma/genética , Adenoma/patologia , Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA/genética , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica/métodos , Instabilidade de Microssatélites , Mutação , SíndromeRESUMO
PURPOSE: Anticoagulation therapy with coumarins necessitates a strict individualization of dosing. Whereas the impacts of the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) polymorphisms on warfarin dosing are clearly established, the role of these genetic variants on dosing and the safe use of phenprocoumon are less well investigated and, to a certain degree, controversial. METHODS: We studied the most frequent functional polymorphisms of VKORC1, CYP2C9, and CYP3A5 in 60 consecutive patients demonstrating complicated phenprocoumon-mediated anticoagulation and in 120 controls. RESULTS: The frequencies of the less active VKORC1 haplotype A-group alleles (p < 0.0001) and of CYP2C9 genotypes with two variant alleles (p = 0.035) were higher in the patient cohort than in the control group, while the frequency of patients carrying only one variant CYP2C9 allele was unchanged relative to the control subjects (RR 1.2; p = 0.49). CONCLUSION: The data suggest a fundamental role of VKORC1 haplotypes and a minor role of CYP2C9 variants in the anticoagulation property of phenprocoumon.
Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Citocromo P-450 CYP3A/genética , Oxigenases de Função Mista/genética , Femprocumona/administração & dosagem , Femprocumona/farmacocinética , Polimorfismo Genético , População Branca/genética , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Citocromo P-450 CYP2C9 , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Frequência do Gene , Genótipo , Alemanha , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Vitamina K Epóxido RedutasesRESUMO
Attempts have been made to elevate excitatory amino acid transporter 2 (EAAT2) expression in an effort to compensate for loss of function and expression associated with disease or pathology. Increased EAAT2 expression has been noted following treatment with beta-lactam antibiotics, and during ischemic preconditioning (IPC). However, both of these conditions induce multiple changes in addition to alterations in EAAT2 expression that could potentially contribute to neuroprotection. Therefore, the aim of this study was to selectively overexpress EAAT2 in astrocytes and characterize the cell type specific contribution of this transporter to neuroprotection. To accomplish this we used a recombinant adeno-associated virus vector, AAV1-glial fibrillary acidic protein (GFAP)-EAAT2, designed to selectively drive the overexpression of EAAT2 within astrocytes. Both viral-mediated gene delivery and beta-lactam antibiotic (penicillin-G) treatment of rat hippocampal slice cultures resulted in a significant increase in both the expression of EAAT2, and dihydrokainate (DHK) sensitive glutamate uptake. Penicillin-G provided significant neuroprotection in rat hippocampal slice cultures under conditions of both moderate and severe oxygen glucose deprivation (OGD). In contrast, viral-mediated overexpression of EAAT2 in astrocytes provided enhanced neuroprotection only following a moderate OGD insult. These results indicate that functional EAAT2 can be selectively overexpressed in astrocytes, leading to enhanced neuroprotection. However, this cell type specific increase in EAAT2 expression offers only limited protection compared to treatment with penicillin-G.
Assuntos
Astrócitos/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Expressão Gênica/fisiologia , Glucose/deficiência , Hipóxia/prevenção & controle , Adenoviridae/fisiologia , Análise de Variância , Animais , Animais Recém-Nascidos , Linhagem Celular Transformada , Transportador 2 de Aminoácido Excitatório/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Humanos , Técnicas In Vitro , Penicilinas/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Transfecção/métodosRESUMO
After osteosynthesis of the proximal humerus by Kirschner wires (K-wire), loosening and secondary loss can occur. This study tested primary fixation of wires made from a shape memory alloy (SMA) Nitinol (NiTi), compared to conventional steel K-wires by pull-out tests. Blocks of cancellous bone were tested with three wire types: NiTi-K-wire with split apex geometry and conventional steel K-wires with and without threads. We found that NiTi-wires can be pulled out of bone more easily than steel wires (P=0.05), even though the former had rougher surfaces. The application of NiTi-wires through bone produced no better stability in comparison to normal steel K-wires, because of triggering the memory effect. Further studies are required to determine if NiTi wires of another appropriate design, surface and localization are superior to conventional wires in the context of this application.
Assuntos
Ligas , Fios Ortopédicos , Animais , Fenômenos Biomecânicos , Osso e Ossos/fisiologia , Cadáver , Bovinos , Desenho de Equipamento , Fixação de Fratura/instrumentação , Fixação de Fratura/métodos , Microscopia Eletrônica de Varredura/métodos , Modelos Animais , Propriedades de SuperfícieAssuntos
Neoplasias Colorretais/patologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/secundário , Pelve Renal/patologia , Idoso , Neoplasias Colorretais/diagnóstico por imagem , Feminino , Humanos , Neoplasias Renais/diagnóstico por imagem , Pelve Renal/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , RadiografiaRESUMO
CD101 exerts negative-costimulatory effects in vitro, but its function in vivo remains poorly defined. CD101 is abundantly expressed on lymphoid and myeloid cells in intestinal tissues, but absent from naïve splenic T cells. Here, we assessed the impact of CD101 on the course of inflammatory bowel disease (IBD). Using a T-cell transfer model of chronic colitis, we found that in recipients of naïve T cells from CD101(+/+) donors up to 30% of the recovered lymphocytes expressed CD101, correlating with an increased interleukin (IL)-2-mediated FoxP3 expression. Transfer of CD101(-/-) T cells caused more severe colitis and was associated with an expansion of IL-17-producing T cells and an enhanced expression of IL-2Rα/ß independently of FoxP3. The co-transfer of naïve and regulatory T cells (Treg) protected most effectively from colitis, when both donor and recipient mice expressed CD101. Although the expression of CD101 on T cells was sufficient for Treg-function and the inhibition of T-cell proliferation, sustained IL-10 production required additional CD101 expression by myeloid cells. Finally, in patients with IBD a reduced CD101 expression on peripheral and intestinal monocytes and CD4(+) T cells correlated with enhanced IL-17 production and disease activity. Thus, CD101 deficiency is a novel marker for progressive colitis and potential target for therapeutic intervention.
Assuntos
Antígenos CD/imunologia , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Interleucina-17/imunologia , Glicoproteínas de Membrana/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Transferência Adotiva , Animais , Antígenos CD/genética , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Colo/imunologia , Colo/patologia , Doença de Crohn/genética , Doença de Crohn/patologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/genética , Interleucina-2/genética , Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade beta de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Ativação Linfocitária , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Índice de Gravidade de Doença , Transdução de Sinais , Linfócitos T Reguladores/patologia , Linfócitos T Reguladores/transplante , Células Th17/patologia , Células Th17/transplanteRESUMO
OBJECTIVES: This study sought to elucidate the short-term efficacy and intermediate-term outcome of excimer laser recanalization of chronic coronary artery occlusions in patients in whom attempts at mechanical revascularization had failed. BACKGROUND: Recanalization of chronic coronary occlusions with the use of a mechanical guide wire fails in 30% to 50% of cases, mostly because of inability to pass the wire through the lesion. The value of using excimer laser energy in this setting has not yet been determined. METHODS: The study group comprised 66 consecutive patients with 68 chronic coronary occlusions. Patients were eligible for inclusion in the study if a previous attempt at mechanical revascularization had failed and if their angiographic status was such that 1) the vessel segment distal to the occlusion could be visualized by way of collateral vessels, 2) the entry point of the occlusion was clearly outlined, and 3) not more than one anatomic bend was expected within the occlusion. Excimer laser energy was applied to the lesion through a 0.018-in. (0.046 cm) fiber-optic guide wire. Adjunctive balloon angioplasty and stenting were performed in all successfully treated patients but one. RESULTS: Thirty-four occlusions (50%) in 32 patients (48%) could be crossed with the laser wire. Location and age of the occlusion had no adverse influence on the outcome of laser wire recanalization, nor did the presence of bridging collateral vessels, a major side branch at the site of the lesion or a blunt stump of the occlusion. An inverse relation was found between the success rate and the length of the occlusion, such that a 19% reduction of the success rate accompanied each 10-mm increment of the mean occlusion length. Thus, the success rate was 68% for lesions < or = 10 mm but only 25% for lesions > 30 to < or = 40 mm. The presence of a bend in the lesion exceeding 60 degrees was strongly related to procedural failure. During a median angiographic follow-up period of 18 weeks, restenosis > 50% (n = 6) or reocclusion (n = 4) was found in 10 of the 32 successfully treated patients, for an intermediate-term success rate of 33% (22 of 66). Clinical follow-up revealed improved anginal status in 21 patients (66%) after a median of 24 weeks. Major complications (death, myocardial infarction, emergency operation) were not encountered. CONCLUSIONS: Successful recanalization of a chronic coronary occlusion by using currently available laser wires can be expected in 50% of selected patients in whom attempts at mechanical revascularization fail. Restenosis or reocclusion accounts for an overall 6-month success rate of 35%.
Assuntos
Angioplastia a Laser , Doença das Coronárias/cirurgia , Angioplastia Coronária com Balão , Angioplastia com Balão a Laser , Angioplastia a Laser/instrumentação , Angioplastia a Laser/métodos , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/terapia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: This study was designed to determine and assess factors predictive of the intermediate-term outcome of stenting of nonacute total coronary occlusions. BACKGROUND: Balloon angioplasty of recanalized coronary occlusions is associated with a combined restenosis/reocclusion rate of up to 65%. Adjunctive stenting holds the potential to reduce this rate significantly. However, variables affecting the late angiographic outcome of coronary stenting in the setting of a total occlusion have not been elucidated sufficiently. METHODS: Coronary stenting was performed in 143 consecutive patients with a nonacute total occlusion; 120 of these patients (84%), with a total of 121 occlusions, underwent repeat angiography within 6 months and comprised the study group. High pressure stent implantation aimed to cover the site of the occlusion as well as adjacent diameter stenoses > or = 70% and all possibly induced dissections. Pertinent angiographic and procedural variables obtained at the time of the intervention were entered into a multivariate logistic regression analysis model to assess their influence on the angiographic outcome at follow-up. RESULTS: Mean preinterventional reference lumen diameter for the 121 vessels was 2.99 +/- 0.53 mm (mean +/- SD); occlusion length ranged from 4 to 44 mm (median of 7.7). After balloon angioplasty, dissections were found in 80% of patients. Lesions were covered with stents a median of 16 mm in length (range 8 to 53). The minimal lumen diameter (MLD) achieved after stenting was 2.89 +/- 0.48 mm. After a median follow-up period of 4.5 months, mean MLD was assessed at 1.91 +/- 0.90 mm, corresponding to a loss index of 0.34 +/- 0.31. There were 27 vessels with a nonocclusive restenosis > or = 50% and 8 with a reocclusion, for a combined restenosis/reocclusion rate of 29%. Factors found to adversely influence angiographic outcome were a post-stenting MLD < or = 2.54 mm, a stented vessel segment length > 16 mm, a balloon/vessel diameter ratio for final stent expansion < or = 1.00 and the presence of a dissection after balloon angioplasty. CONCLUSIONS: Compared with previous reports on stand-alone balloon angioplasty, stenting of nonacute total coronary occlusions lowers the 6-month restenosis/reocclusion rate to approximately 30%. The late procedural outcome is independently and statistically significantly influenced by the MLD after stenting, the length of the stented vessel segment, the balloon/vessel diameter ratio for final stent expansion and the incidence of dissections after balloon angioplasty.
Assuntos
Angiografia Coronária , Doença das Coronárias/terapia , Stents , Análise de Variância , Dissecção Aórtica/etiologia , Dissecção Aórtica/terapia , Angioplastia Coronária com Balão/efeitos adversos , Distribuição de Qui-Quadrado , Estudos de Coortes , Aneurisma Coronário/etiologia , Aneurisma Coronário/terapia , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/patologia , Vasos Coronários/patologia , Feminino , Seguimentos , Previsões , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva , Fatores de Risco , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
OBJECTIVES: This retrospective study was designed to determine the six-month angiographic outcome after stenting of native coronary arteries in insulin-treated (ITDM) and non-ITDM patients with diabetes mellitus (DM) and compare the results with those in non-DM patients. BACKGROUND: The influence of the treatment modality for DM on restenosis in patients undergoing coronary artery stenting has not been elucidated sufficiently. METHODS: A total of 1,439 (70%) of 2,061 patients underwent repeated angiography within six months of coronary stenting. The ITDM and non-ITDM (oral hypoglycemic drugs or diet) were documented in 48 (3.3%) and 177 patients (12.3%), respectively, leaving 1,214 non-DM patients. RESULTS: Baseline reference vessel diameter tended to be smaller in ITDM patients (mean, 2.73 mm) than in non-DM and non-ITDM patients (2.88 mm and 2.85 mm, respectively). However, percent diameter stenosis was not different. The median number of stents deployed was 1; median stent length was 15 mm. Statistically significant differences were present after stenting for the means of minimal lumen diameter (MLD) and acute gain between ITDM patients (MLD: 2.67 mm, acute gain: 1.98 mm) and non-DM patients (MLD: 2.81 mm, acute gain: 2.16 mm). At follow-up, percent diameter stenosis, late lumen loss and loss index were significantly higher in both non-ITDM lesions (42%, 1.14 mm and 0.56, respectively) and ITDM lesions (48%, 1.26 mm and 0.65, respectively) than in non-DM lesions (35%, 0.96 mm and 0.45, respectively). The corresponding differences between non-ITDM and ITDM lesions did not reach statistical significance. Restenosis rates in non-DM, non-ITDM and ITDM lesions were 23.8%, 32.8% (p = 0.013 vs. non-DM) and 39.6% (p = 0.02 vs. non-DM, p = 0.477 vs. non-ITDM), respectively. CONCLUSIONS: This study showed that compared with stenting in non-DM patients, stenting of native coronary arteries in DM patients is associated with significantly increased lumen renarrowing, regardless of the treatment modality for DM.
Assuntos
Angioplastia Coronária com Balão , Doença das Coronárias/terapia , Angiopatias Diabéticas/terapia , Stents , Idoso , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/mortalidade , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Diabetes Mellitus Tipo 1/mortalidade , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/terapia , Angiopatias Diabéticas/diagnóstico por imagem , Angiopatias Diabéticas/mortalidade , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Excimer laser angioplasty with adjunctive percutaneous transluminal coronary angioplasty of chronic coronary artery occlusions was performed using the Litvack 1.3 Z laser catheter in 80 patients in whom the occlusion could be passed by a guidewire; success rate was 89%. Angiographic follow-up revealed a restenosis rate of 33% and a reocclusion rate of 20%, and clinical follow-up showed a significant symptomatic improvement. It is concluded that laser angioplasty is a promising method for the treatment of chronic coronary artery occlusions.
Assuntos
Angioplastia Coronária com Balão , Doença das Coronárias/terapia , Idoso , Angioplastia com Balão a Laser , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RecidivaRESUMO
Sexual harassment among adolescents has long been neglected in Germany though it is frequent and leads to significant strain for the victims. In international studies, the prevalence of sexual harassment ranges from 10 to 80â% among students. For the development of sexual harassment individual as well as school based factors play a role. Different pathways lead to this problematic behaviour. The effect of new media in the development of sexual harassment cannot be estimated so far. Frequent consequences of sexual harassment in addition to school associated difficulties are unspecific somatic complaints. General practitioners and pediatricians are frequently consulted tn the first place. Recommendations for consultation and interventions are presented.