RESUMO
Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET- sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET- patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET- cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. Clinical trial number: EORTC 90101, NCT01524926.
Assuntos
Antineoplásicos/uso terapêutico , Crizotinibe/uso terapêutico , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Adolescente , Adulto , Idoso , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Feminino , Rearranjo Gênico , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/mortalidade , Adulto JovemRESUMO
BACKGROUND: To determine the activity of radiotherapy in patients with inoperable desmoid-type fibromatosis (DF) a multicenter prospective phase II trial was carried out. MATERIALS AND METHODS: Patients with inoperable progressive disease of primary, recurrent or incompletely resected lesions received a dose of 56 Gy in 28 fractions. Follow-up MRI studies were carried out every 3 months for 2 years and thereafter every 6 months. The primary end point was local control rate at 3 years, estimated by a nonparametric method for interval-censored survival data. Secondary end points were objective tumor response, acute and late toxic effect. RESULTS: Forty-four patients (27 F/17 M) were enrolled from 2001 to 2008. Median age was 39.5 years. Main tumor sites included trunk 15 (34.1%) and extremities 27 (61.3%). Median follow-up was 4.8 years. The 3-year local control rate was 81.5% (90% one-sided confidence interval 74% to 100%). Best overall response during the first 3 years was complete response (CR) 6 (13.6%), partial response (PR) 16 (36.4%), stable disease 18 (40.9%), progressive disease 3 (6.8%) and nonassessable 1 (2.3%). Five patients developed new lesions. After 3 years, the response further improved in three patients: (CR 2, PR 1). Acute grade 3 side-effects were limited to skin, mucosal membranes and pain. Late toxic effect consisted of mild edema in 10 patients. CONCLUSIONS: Moderate dose radiotherapy is an effective treatment of patients with DF. Response after radiation therapy is slow with continuing regression seen even after 3 years.
Assuntos
Fibromatose Agressiva/radioterapia , Recidiva Local de Neoplasia/radioterapia , Adolescente , Adulto , Idoso , Feminino , Fibromatose Agressiva/diagnóstico por imagem , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Radiografia , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
We demonstrate here that somatic variation of CGG repeat length is based on a mosaic of cells with different but stable FMR-1 alleles and does not reflect permanent mitotic instability. The length of a particular allele in an individual cell was maintained in progeny cells establishing a clone. The mutation patterns of multiple repeats in the DNA of fetal tissues were identical and did not significantly change during proliferation in vitro. It is proposed that genotype mosaicism and expansion to full mutation are generated post-conceptionally by the same molecular mechanism in a particular window of early development.
Assuntos
Desenvolvimento Embrionário e Fetal/genética , Síndrome do Cromossomo X Frágil/genética , Amplificação de Genes , Mitose , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA , Sequências Repetitivas de Ácido Nucleico , Alelos , Diferenciação Celular , Divisão Celular , Células Clonais/patologia , Feminino , Feto/patologia , Fibroblastos/patologia , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil/embriologia , Síndrome do Cromossomo X Frágil/patologia , Humanos , Masculino , Mosaicismo , Placenta/patologiaRESUMO
Extra abdominal desmoid fibromatosis is a complex condition with many recognised treatments including active observation, hormonal therapy, chemotherapy, radiotherapy and surgical resection. There is large variation in the natural history of individual desmoid tumours, with some cases progressing aggressively and others regressing spontaneously when observed alone. This combined with an absence of accurate clinical predictors of a desmoid tumour's behaviour has led to difficulties in identifying which patients would benefit most from aggressive treatment, and which could be adequately managed with a policy of active observation alone. This review explores the aetiology and common presentation of extra-abdominal desmoid fibromatosis including the condition's histopathological, clinical and radiological characteristics. The current evidence for potential predictors of desmoid tumour behaviour is also reviewed, along with the indications and evidence for the multitude of treatments available. We also summarise the published guidelines that are currently available for oncologists and surgeons managing extra-abdominal desmoid fibromatosis, and highlight some of the unanswered questions that need to be addressed to optimise the management of this condition.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia por Agulha , Fibromatose Agressiva/diagnóstico , Fibromatose Agressiva/terapia , Mutação , Equipe de Assistência ao Paciente , Biomarcadores Tumorais/análise , Biópsia por Agulha/instrumentação , Biópsia por Agulha/métodos , Cromossomos Humanos Par 8/genética , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Fibroma/diagnóstico , Fibroma/terapia , Fibromatose Agressiva/diagnóstico por imagem , Fibromatose Agressiva/genética , Fibromatose Agressiva/patologia , Humanos , Terapia de Alvo Molecular , Vigilância da População/métodos , Guias de Prática Clínica como Assunto , Prognóstico , Fatores de Risco , Trissomia/genética , beta Catenina/genéticaRESUMO
AIMS: The optimal management of desmoid fibromatosis remains unclear, leading to significant variability in patient management. To assess this problem, the current approach of clinicians managing this complex condition in the UK was investigated. MATERIALS AND METHODS: A hypothetical case of intramuscular limb girdle desmoid fibromatosis in a fit 65-year-old patient was devised. Surgical and non-surgical oncology members of the British Sarcoma Group were questioned on how they would manage this case in three scenarios: primary disease with function-sparing surgery possible, primary disease with neurovascular involvement and disease recurrence after a previous R0 resection. Initial management, management of symptomatic disease progression, follow-up preferences and any differences in respondents' management choices in a younger case were investigated. RESULTS: The responses from 14 sarcoma surgeons and 23 oncologists (14 clinical, nine medical) were analysed. Desmoid fibromatosis management is generally shared by surgeons and oncologists within sarcoma multidisciplinary teams in the UK. Variation exists in the chosen initial management of primary desmoid fibromatosis in the UK, with function-sparing surgery possible (observation 51%, resection 51%), primary desmoid fibromatosis with neurovascular involvement (hormone therapy with non-steroidal anti-inflammatory drugs 51%, radiotherapy 27%, observation 22%) and for cases of desmoid fibromatosis recurrence (radiotherapy 41%, hormone therapy and non-steroidal anti-inflammatory drugs 27%, observation 24%). There was a clear preference of surgical resection of symptomatic disease progression in cases of primary desmoid fibromatosis without neurovascular involvement (60%). By contrast, radiotherapy was the preferred treatment for progression in cases with neurovascular involvement (47%) or cases of recurrence after a previous R0 resection (34%). Clinical follow-up was selected 3 months after intervention in 68% of scenarios. Follow-up imaging was selected 3 or 6 months after intervention in 57% and 21% of cases, respectively. Most respondents would not change their chosen management in younger patients. DISCUSSION: Several groups have issued formal guidelines for clinicians managing desmoid fibromatosis, including the British Sarcoma Group, the National Comprehensive Cancer Network and the European Society for Medical Oncology. However, these are in some ways contradictory and may not reflect recent publications, potentially explaining the significant variation in the management of desmoid fibromatosis in the UK shown by this survey. We propose a review of current evidence; a national consensus or a desmoid fibromatosis registry may help to standardise desmoid fibromatosis care.
Assuntos
Gerenciamento Clínico , Fibromatose Agressiva/prevenção & controle , Idoso , Terapia Combinada , Progressão da Doença , Humanos , Prognóstico , Reino UnidoRESUMO
Current research in the field of medical decision making tries to represent and to analyse complex, uncertain and complicated situations. The first version of DIABETEX, which is a decision support system for the treatment of diabetic out-patients, accepts the challenge to overcome these difficulties. It includes a network of rules on the basis of known glucose-insulin relationships under different situations. The insulin dose for type I diabetic patients is suggested accordingly. In this, the application of special cybernetic methods offers the chance to overcome complexity, uncertainty, fuzzyness and incompleteness of data. Two methods of classification are presented to complete the DIABETEX decision unit: (1) the Bayes' classification is used in the calculation of insulin doses for type I diabetic patients on multiple subcutaneous insulin injections considering the basis-bolus concept; (2) fuzzy classification is employed in separating 'normal diabetic days' from days with information on special situations such as exercise, illness, menstruation on the one side, from stress, hypoglycaemia etc. on the other.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Insulina/administração & dosagem , Software , Teorema de Bayes , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Esquema de Medicação , Ingestão de Alimentos/fisiologia , Sistemas Inteligentes , HumanosRESUMO
In the course of an experimental study 12 pigs were infected intrabronchially with the pathogen of infectious porcine pleuropneumonia, Actinobacillus pleuropneumoniae. All animals survived the acute stage of infection due to the application of subtherapeutic doses of antibiotics. After infection all of the animals showed clinical signs of acute pneumonia with an elevation of body temperature to about 41 degrees C. Bronchoalveolar lavage fluid (BALF) was taken every week endoscopically. An increase of neutrophil granulocytes could be observed at day 7 and 14 after infection. In parallel, a clear granulocytosis and a shift to the left of the nuclei was observed at day 7. Comparing the methods for detection of Actinobacillus pleuropneumoniae serological assays like the complement-fixation assay (CFA) and enzyme-linked immunosorbent assay (ELISA) as well as immunofluorescence in lung tissue and BALF were more sensitive than cultural isolation from lung tissue, tonsils and BALF.
Assuntos
Infecções por Actinobacillus/veterinária , Actinobacillus pleuropneumoniae , Pleuropneumonia/veterinária , Doenças dos Suínos , Infecções por Actinobacillus/diagnóstico , Infecções por Actinobacillus/fisiopatologia , Animais , Temperatura Corporal , Líquido da Lavagem Broncoalveolar/microbiologia , Testes de Fixação de Complemento , Ensaio de Imunoadsorção Enzimática , Febre , Pulmão/microbiologia , Pulmão/patologia , Masculino , Tonsila Palatina/microbiologia , Tonsila Palatina/patologia , Pleuropneumonia/diagnóstico , Pleuropneumonia/fisiopatologia , Sensibilidade e Especificidade , SuínosRESUMO
Hypoxia is an important factor in tumor growth. It is associated with resistance to conventional anticancer treatments. Gene therapy targeting hypoxic tumor cells therefore has the potential to enhance the efficacy of treatment of solid tumors. Transfection of a panel of tumor cell lines with plasmid constructs containing hypoxia-responsive promoter elements from the genes, vascular endothelial growth factor (VEGF) and erythropoietin, linked to the minimal cytomegalovirus (mCMV) or minimal interleukin-2 (mIL-2) promoters showed optimum hypoxia-inducible luciferase reporter gene expression with five repeats of VEGF hypoxic-response element linked to the mCMV promoter. Adenoviral vectors using this hypoxia-inducible promoter to drive therapeutic transgenes produced hypoxia-specific cell kill of HT1080 and HCT116 cells in the presence of prodrug with both herpes simplex virus thymidine kinase/ganciclovir and nitroreductase (NTR)/CB1954 prodrug-activating systems. Significant cytotoxic effects were also observed in patient-derived human ovarian cancer cells. The NTR/CB1954 system provided more readily controllable transgene expression and so was used for in vivo experiments of human HCT116 xenografts in nude mice. Subjects treated intratumorally with Ad-VEGFmCMV-NTR and intraperitoneal injection of CB1954 demonstrated a statistically significant reduction in tumor growth. Immunohistochemistry of treated xenografts showed a good correlation between transgene expression and hypoxic areas. Further investigation of these hypoxia-inducible adenoviral vectors, alone or in combination with existing modalities of cancer therapy, may aid in the future development of successful Gene-Directed Enzyme Prodrug Therapy systems, which are much needed for targeting solid tumors.
Assuntos
Adenoviridae/genética , Terapia Genética/métodos , Fator 1 Induzível por Hipóxia/genética , Nitrorredutases/genética , Pró-Fármacos/farmacocinética , Timidina Quinase/genética , Adenoviridae/metabolismo , Animais , Hipóxia Celular/genética , Linhagem Celular Tumoral , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Células HCT116 , Células HEK293 , Humanos , Fator 1 Induzível por Hipóxia/biossíntese , Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Nitrorredutases/metabolismo , Pró-Fármacos/administração & dosagem , Simplexvirus/enzimologia , Simplexvirus/genética , Timidina Quinase/biossíntese , Timidina Quinase/metabolismo , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The Y chromosome of Drosophila carries fertility genes which, in part, develop lampbrush loops during the meiotic prophase. Hybrid males from crosses between D. hydei and D. neohydei are fertile although the morphology of the lampbrush loops differs between both species. With the aid of X ray induced "hybrid" X-Y translocation chromosomes the question has been studied whether Y chromosomal genes of D. neohydei can substitute deletions in the Y chromosome of D. hydei. Although the induction of translocation chromosomes almost regularly results in an inactivation of the translocated Y fragment within a few generations, one case of successful complementation has been demonstrated. Furthermore, a new lampbrush loop pair has been detected in D. neohydei which is morphologically similar to the "nooses" of D. hydei. Preliminary evidence for the location of the lampbrush loops on the Y chromosome of D. neohydei is discussed.
Assuntos
Drosophila/genética , Cromossomos Sexuais/fisiologia , Regulação da Expressão Gênica , Teste de Complementação Genética , Masculino , Meiose , Cromossomos Sexuais/ultraestrutura , Espermatogênese , Translocação GenéticaRESUMO
The persistence of Actinobacillus pleuropneumoniae in convalescent pigs significantly contributes to the distribution of disease. The downregulation of protective antigens in vivo as one possible mechanism responsible for this phenomenon was investigated using the small iron-regulated transferrin binding protein (TbpB-protein) as exemplary protective antigen. From a total of 21 pigs experimentally infected with A. pleuropneumoniae serotype 7 in three trials, bronchoalveolar lavage fluid (BALF) was obtained on day 1 or 2, day 7, day 14 and day 21. Employing double immunofluorescence of BALF with a monoclonal anti-TbpB antibody and an A. pleuropneumoniae -specific anti-polysaccharide antiserum a statistically significant decrease of the percentage of A. pleuropneumoniae bacteria strongly expressing TbpB protein was observed during the course of infection. These results were supported by in vitro incubation of A. pleuropneumoniae in medium supplemented with BALF. In addition, it was found that TbpB-expression in BALF from day 7 after infection could not be inhibited by the substitution of iron. These results suggest (i) the downregulation of protective antigens is one possible mechanism allowing bacterial persistence, (ii) in vitro induction in the presence of BALF mimics the in vivo situation, and (iii) TbpB expression is additionally regulated by an iron-independent mechanism.
Assuntos
Infecções por Actinobacillus/veterinária , Actinobacillus pleuropneumoniae/imunologia , Antígenos de Bactérias/imunologia , Proteínas de Transporte/imunologia , Pleuropneumonia/veterinária , Doenças dos Suínos/imunologia , Infecções por Actinobacillus/imunologia , Infecções por Actinobacillus/microbiologia , Actinobacillus pleuropneumoniae/patogenicidade , Animais , Anticorpos Monoclonais , Antígenos de Bactérias/genética , Western Blotting/veterinária , Lavagem Broncoalveolar/veterinária , Proteínas de Transporte/genética , Densitometria/veterinária , Regulação para Baixo , Eletroforese em Gel de Poliacrilamida/veterinária , Feminino , Fluorimunoensaio/veterinária , Regulação Bacteriana da Expressão Gênica , Ferro/análise , Proteínas de Ligação ao Ferro , Pulmão/imunologia , Masculino , Tonsila Palatina/imunologia , Pleuropneumonia/imunologia , Pleuropneumonia/microbiologia , Distribuição Aleatória , Proteínas Recombinantes/imunologia , Suínos , Doenças dos Suínos/microbiologia , Proteínas de Ligação a TransferrinaRESUMO
The clinical and histological findings in a 54-year-old patient with enteropathy-associated T-cell lymphoma (EATL) occurring 18 years after renal transplantation are presented. Ten years after adult-onset coeliac disease the patient developed medium to large T-cell non-Hodgkin's lymphoma of the small intestine. Epstein-Barr virus (EBV) genome was detected by polymerase chain reaction in the lymphoma tissue and localized via Epstein-Barr virus RNAs in situ hybridization to some of the tumour cells. This is the first case report of EBV-positive EATL occurring in the setting of immunosuppression.
Assuntos
Linfoma de Burkitt/complicações , Herpesvirus Humano 4/fisiologia , Neoplasias Intestinais/complicações , Transplante de Rim/patologia , Linfoma de Células T/complicações , Sequência de Bases , Linfoma de Burkitt/química , Linfoma de Burkitt/patologia , DNA Viral/análise , DNA Viral/genética , Feminino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Humanos , Terapia de Imunossupressão , Hibridização In Situ , Neoplasias Intestinais/química , Neoplasias Intestinais/patologia , Intestino Delgado/química , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Linfoma de Células T/química , Linfoma de Células T/patologia , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , RNA Viral/análise , RNA Viral/genéticaRESUMO
Epstein-Barr virus (EBV)-genome containing cases of Hodgkin's disease (HD) are known to express latent membrane protein (LMP) of EBV but no EBV nuclear antigen 2 (EBNA2). We investigated 35 cases of HD for the presence of EBV genome sequences to know whether EBNA2 coding region is deleted in HD. 27 cases had general EBV sequences, none had evidence of a deletion of EBNA2. 26 cases turned out to harbour EBV type 1, one case had EBV type 2. The absence of EBNA2 protein expression in HD can not be explained by a deletion of EBNA2 coding region. EBV type 1 is the prevalent subtype of EBV in our series of HD.
Assuntos
Antígenos Virais/genética , Proteínas de Ligação a DNA/genética , Genoma Viral , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Doença de Hodgkin/microbiologia , Síndrome da Imunodeficiência Adquirida/complicações , Mapeamento Cromossômico , Antígenos Nucleares do Vírus Epstein-Barr , Herpesvirus Humano 4/imunologia , Doença de Hodgkin/complicações , Doença de Hodgkin/patologia , Humanos , Linfoma não Hodgkin/microbiologia , Linfoma não Hodgkin/patologiaRESUMO
Primary human neoplasms were examined for the presence of substance-P receptors by receptor autoradiography with 125I-labelled Bolton-Hunter substance P. Substance-P receptors were localized and characterized in the neoplastic cells of 9/12 astrocytomas, 10/10 glioblastomas, 10/12 medullary thyroid carcinomas, 8/16 breast carcinomas and 4/5 ganglioneuroblastomas. Conversely, substance-P receptors were not or only rarely identified on non-small-cell carcinomas of the lung (1/16), neuroblastomas (0/8), adenocarcinomas of the colon (1/21) or the pancreas (1/9), or on malignant lymphomas (3/18). However, in the great majority of the investigated tumours, substance-P receptors were found on intra- and peritumoral blood vessels. All substance-P receptors detected had the pharmacological characteristics of the neurokinin-I receptor sub-type. In addition, the expression of somatostatin receptors was examined in all the neoplastic tissues mentioned above. Both substance-P and somatostatin receptors were present in astrocytomas and in ganglioneuroblastomas, whereas little or no receptor was found in pancreatic and non-small-cell lung carcinomas. The extent of somatostatin-receptor expression was inversely correlated to that of the substance-P receptors in glioblastomas, neuroblastomas and non-Hodgkin's lymphomas. The tumoral and vascular localization of substance-P receptors in tumours may have clinical implications. The use of radiolabelled substance P for in vivo scintigraphy may supplement the current set of diagnostic tools. Substance-P antagonists might be used in the treatment of tumours, as their binding to vascular receptors may decrease tumoral blood supply and drainage.
Assuntos
Neoplasias/química , Receptores da Neurocinina-1/análise , Autorradiografia , Vasos Sanguíneos/química , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Ensaio Radioligante , Receptores de Somatostatina/análiseRESUMO
Lethal midline granuloma (LMG) is associated with Epstein-Barr virus (EBV). The latter has at least two subtypes with different biological properties. The subtypes can be identified by their genomic configuration. Using EBV-RNA (EBER) in situ hybridization and EBV polymerase chain reaction (PCR), we have looked for the presence of EBV in six LMGs and six non-Hodgkin's lymphomas (NHLs) located in the nasopharyngeal region, and determined the subtype of EBV. Six of six LMGs were positive by PCR and EBER in situ hybridization, whereas NHLs were either negative or, in three of six cases, showed few EBER-positive cells considered to be nonneoplastic lymphocytes. The subtype 2 was found in LMG lesions of three of six patients; the remaining three of six patients with LMG had the generally occurring subtype 1. The results indicate that the association of EBV with NHL may depend more on tumor type than on its localization. The occurrence of the rare subtype 2 in LMG may relate to a covert immune defect.
Assuntos
Granuloma Letal da Linha Média/microbiologia , Herpesvirus Humano 4/patogenicidade , Linfoma de Células T/imunologia , Idoso , Sequência de Bases , Criança , Pré-Escolar , DNA Viral/análise , Feminino , Genes Virais , Herpesvirus Humano 4/química , Herpesvirus Humano 4/classificação , Humanos , Imunofenotipagem , Hibridização In Situ , Masculino , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos/química , Reação em Cadeia da Polimerase , Provírus/química , RNA Viral/análise , Proteínas Estruturais Virais/genéticaRESUMO
BACKGROUND & AIMS: Neuropeptide receptors, expressed at high density by neoplastic cells, can be instrumental for diagnosis and therapy. However, little is known about neuropeptides and neuropeptide receptors in the tumor bed. The aim of this study was to study the expression of two neuropeptide receptors in peritumoral blood vessels. METHODS: Somatostatin and substance P receptors were measured using in vitro receptor autoradiography in well-defined submucosal and subserosal vessels located in the immediate surroundings of human colorectal carcinomas or in normal colon taken at increasing distances from the tumor. RESULTS: Both receptors were 3-5-fold overexpressed in the host veins within a 2-cm-wide area surrounding human primary colorectal carcinomas compared with veins located at 5-10-cm distance in normal gut tissue. The expression of peritumoral vascular somatostatin receptor and substance P receptor appears independent of receptor expression in the tumor, of tumor stage, and of the grade of local inflammation. CONCLUSIONS: These biochemical alterations of veins in the immediate vicinity of tumors represent a novel tumor-related site of expression for the two receptors and may point to a new biological principle of host-tumor interaction. Thus, vascular regulatory mechanisms in the tumor bed may be important for tumor development and metastasis and may be used as a target for tumor therapy.
Assuntos
Neoplasias Colorretais/irrigação sanguínea , Receptores da Neurocinina-1/metabolismo , Receptores de Somatostatina/metabolismo , Regulação para Cima , Idoso , Idoso de 80 Anos ou mais , Autorradiografia , Vasos Sanguíneos/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Tissue samples of 21 HIV-positive patients have been studied for the presence and distribution of Epstein-Barr virus (EBV) subtypes A and B. This was done by PCR, EBER in situ hybridization, and immunohistochemical detection of EBV latent membrane protein (LMP) in AIDS-associated malignant lymphomas (16 cases) and lymphatic organs of patients without lymphoma (5 cases). Eleven cases were considered to be EBV-positive, with type A in four, and type B virus in four other cases. In patients with malignant lymphoma, EBV was localized in tumour tissue exclusively. One patient without lymphoma presented with multiple EBV genome type B-positive cells in all the lymphoid tissue samples examined. In HIV-positive patients, both subtypes of EBV, A and B, may play a role in the pathogenesis of lymphoproliferative lesions.
Assuntos
Infecções por HIV/microbiologia , Herpesvirus Humano 4/isolamento & purificação , Tecido Linfoide/microbiologia , Linfoma Relacionado a AIDS/microbiologia , Adulto , Idoso , Feminino , Herpesvirus Humano 4/classificação , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
Interleukin-12 (IL-12), a cytokine with in vitro and in vivo immunomodulatory effects, is produced by lymphocytes and stimulated monocytes. Little is known about the production and possible role of IL-12 in human lymphoproliferative disorders. We examined IL-12 expression by immunohistochemistry using antibodies recognizing the p40, p35 subunits, and the p70 heterodimeric IL-12 protein, and by Northern blot in lymph nodes from patients with Hodgkin's disease (HD), non-Hodgkin's lymphomas (NHL), and nonneoplastic lymphoid lesions. In the majority of the HD cases (28 of 34), IL-12 immunoreaction was found in small lymphoid cells cultured around Hodgkin and Reed-Sternberg (H&RS) cells. No IL-12 signal was seen in H&RS cells. Transcripts for IL-12 were found by Northern and dot blot analysis in 13 of 19 (IL-12 p40) and 11 of 19 (IL-12 p35) cases. The HD cases were further examined for the presence of Epstein-Barr virus (EBV) latent membrane protein (LMP-1). All cases with EBV-LMP-1 positivity (22 of 34 cases) also expressed IL-12. No IL-12 immunoreaction was found in neoplastic cells of 33 cases of various NHLs, which were all LMP-1 negative and showed no EBV-genome sequence, as assessed by polymerase chain reaction (PCR). In 24 nonneoplastic lymphoid lesions, few dispersed IL-12 positive cells were seen in the parafollicular area and in the sinus of the lymph node. The marked presence of IL-12 in the majority of HD cases indicates that IL-12 might play a role in the pathobiology of HD, suggesting that this cytokine is involved in EBV-positive HD.
Assuntos
Herpesvirus Humano 4/patogenicidade , Doença de Hodgkin/virologia , Interleucina-12/biossíntese , Linfadenite/genética , Linfoma/genética , Proteínas de Neoplasias/biossíntese , Biomarcadores/análise , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/patologia , Infecções por Herpesviridae/virologia , Herpesvirus Humano 4/isolamento & purificação , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Humanos , Hiperplasia , Interleucina-12/genética , Linfonodos/metabolismo , Linfonodos/patologia , Linfadenite/patologia , Linfoma/patologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Proteínas de Neoplasias/genética , RNA Mensageiro/análise , RNA Neoplásico/análise , Células de Reed-Sternberg/patologia , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/patologia , Infecções Tumorais por Vírus/virologia , Proteínas da Matriz Viral/análiseRESUMO
OBJECTIVE: TCL1, MTCP1 and TCL1b are three members of a new family of oncogenes that are expressed in T cell leukemias of ataxia telangiectasia patients (T-PLL, T-CLL). TCL1 is located at 14q32.1 and activated by juxtaposition to the alpha/delta-locus at 14q11 or beta-locus at 7q35 of the T cell receptor during the reciprocal translocations t(14;14)(q11;q32), t(7;14)(q35;q32), or inversion inv(14)(q11;q32). TCL1 encodes a predominantly cytoplasmic protein of 114 aa (14 kD) of unknown function. Recent studies suggest that TCL1 promotes cell survival rather than stimulating cell proliferation, as previously proposed. METHODS: In an attempt to clarify the contexts in which TCL1 is expressed, we investigated TCL1 expression in 114 lymphoma and leukemia patients by Northern blot, RT-PCR and immunohistochemistry. RESULTS: TCL1 expression is restricted to lymphoid cells, and is found in neoplastic (T and B cell neoplasms, and Hodgkin's disease) and nonneoplastic proliferations (reactive lesions). Out of 114 cases, 18 neoplasms of myeloid and 4 cases of epithelial origin were TCL1-negative. In lesions of the lymphoid system, both low- and high-grade lymphomas were found to express TCL1. CONCLUSIONS: We propose that TCL1 expression especially in high-grade B cell non-Hodgkin's lymphomas might interfere with B cell differentiation and promote the transition from low- to high-grade lymphoma.