RESUMEN
BACKGROUND: Enrolling patients in studies of pancreatic ductal adenocarcinoma (pdac) is challenging because of the high fatality of the disease. We hypothesized that a prospective clinic-based study with rapid ascertainment would result in high participation rates. Using that strategy, we established the Quebec Pancreas Cancer Study (qpcs) to investigate the genetics and causes of pdac and other periampullary tumours (pats) that are also rare and underrepresented in research studies. METHODS: Patients diagnosed with pdac or pat were introduced to the study at their initial clinical encounter, with a strategy to enrol participants within 2 weeks of diagnosis. Patient self-referrals and referrals of unaffected individuals with an increased risk of pdac were also accepted. Family histories, epidemiologic and clinical data, and biospecimens were collected. Additional relatives were enrolled in families at increased genetic risk. RESULTS: The first 346 completed referrals led to 306 probands being enrolled, including 190 probands affected with pdac, who represent the population focus of the qpcs. Participation rates were 88.4% for all referrals and 89.2% for pdac referrals. Family history, epidemiologic and clinical data, and biospecimens were ascertained from 91.9%, 54.6%, and 97.5% respectively of patients with pdac. Although demographics and trends in risk factors in our patients were consistent with published statistics for patients with pdac, the qpcs is enriched for families with French-Canadian ancestry (37.4%), a population with recurrent germ-line mutations in hereditary diseases. CONCLUSIONS: Using rapid ascertainment, a pdac and pat research registry with high participation rates can be established. The qpcs is a valuable research resource and its enrichment with patients of French-Canadian ancestry provides a unique opportunity for studies of heredity in these diseases.
RESUMEN
The aim of this study was to determine the predictive and prognostic value of epidermal growth factor receptor (EGFR) expression in rectal cancers treated with preoperative high-dose rate brachytherapy and in mismatch-repair (MMR)-proficient colorectal cancers (CRCs), respectively. We validate the use of receiver operating characteristic (ROC) curve analysis to select cutoff scores for EGFR overexpression for the end points studied. Immunohistochemistry (IHC) for EGFR was performed on 82 rectal tumour biopsies and 1197 MMR-proficient CRCs using a tissue microarray. Immunoreactivity was scored as the percentage of positive tumour cells by three pathologists and the inter-observer reliability was assessed. ROC curve-derived cutoffs were used to analyse the association of EGFR overexpression, tumour response and several clinicopathological features including survival. The scoring method was found to be reproducible in rectal cancer biopsies and CRCs. The selected cutoff scores from ROC curve analysis for each clinicopathological feature were highly consistent among pathologists. EGFR overexpression was associated with response to radiotherapy (P-value <0.001) and with worse survival time (P-value <0.001). In multivariate analysis, EGFR overexpression was independently associated with adverse prognosis (P-value <0.001). Epidermal growth factor receptor is a predictive marker of response to preoperative radiotherapy and an independent adverse prognostic factor CRC.
Asunto(s)
Adenocarcinoma/metabolismo , Braquiterapia , Neoplasias Colorrectales/metabolismo , Receptores ErbB/metabolismo , Curva ROC , Análisis de Matrices Tisulares , Adenocarcinoma/patología , Adenocarcinoma/radioterapia , Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/radioterapia , Humanos , Inmunohistoquímica , Terapia Neoadyuvante , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Resultado del TratamientoRESUMEN
We have reported previously that naive T cells from relapsing-remitting multiple sclerosis (RRMS) patients have T cell receptor (TCR) repertoire shifts, but the basis of these TCR repertoire shifts was uncertain. Here, we questioned whether RRMS patients have altered naive CD4 and CD8 T cell homeostasis by studying homeostatic proliferation and thymic production in RRMS patients and healthy controls. We measured thymic production by quantifying signal joint T cell receptor excision circles (sjTRECs). Both naive T subsets from controls showed an age-associated decrease in sjTRECs, i.e. evidence of progressive thymic involution, but we detected no age-associated decrease in sjTRECs in RRMS patients. Instead, naive CD8 T cells from patients had lower sjTRECs (P = 0.012) and higher Ki-67 proliferation levels (P = 0.04) than controls. Naive CD4 T cell sjTRECs did not differ between patients and controls. However, in RRMS these sjTRECs correlated strongly with CD31, a marker expressed by newly generated CD4 T cells but not by naive CD4 T cells that have undergone homeostatic proliferation. HLA-DR2 positivity correlated negatively with naive CD4 T cell CD31 expression in RRMS (P = 0.002). We conclude in RRMS that naive T subsets have homeostatic abnormalities due probably to peripheral (non-thymic) mechanisms. These abnormalities could have relevance for MS pathogenesis, as naive T cell changes may precede MS onset.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Homeostasis/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Timo/inmunología , División Celular/inmunología , Reordenamiento Génico de Linfocito T/genética , Reordenamiento Génico de Linfocito T/inmunología , Genes Codificadores de los Receptores de Linfocitos T/genética , Genes Codificadores de los Receptores de Linfocitos T/inmunología , Antígeno HLA-DR2/análisis , Homeostasis/genética , Humanos , Inmunofenotipificación/métodos , Antígeno Ki-67/análisis , Esclerosis Múltiple Recurrente-Remitente/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Receptores Inmunológicos/inmunología , Reproducibilidad de los ResultadosRESUMEN
Autoimmune diseases include a heterogeneous group of complex traits, the causes of which are essentially unknown. The threshold liability model is a hypothesis that has a significant influence on thinking about causation in these diseases. Here, I analyze this model and assess its utility in understanding causation in autoimmunity. According to the model, members of a population have a normal distribution of genetic liability for a particular autoimmune disease. Further, a threshold value exists for each autoimmune disease such that an individual develops disease when his/her liability exceeds the threshold value; environmental and stochastic factors and epistatic gene interactions may increase or decrease an individual's disease liability. There are, however, two main problems with the threshold liability model. First, for a particular autoimmune disease, the threshold value divides a population into two distinct groups that consist either of affected or of healthy individuals. I show that this dichotomous division is inaccurate and misleading. Second, the threshold value corresponds to the occurrence of a component-cause of disease, i.e. when an appropriate collection of causative factors for a particular autoimmune disease is present, the disease must inevitably occur. I argue, however, that the disease contribution of essentially unknown random or stochastic factors to causation is at least similar in importance to the contributions of genetic and environmental factors. These stochastic factors add a significant element of unpredictability to the effects of genetic and environmental factors. Consequently causes in autoimmunity do not act deterministically, which is implied by the component-cause concept. Instead, the role of causative factors is to alter disease risk. I therefore reject the threshold liability model and conclude that a probabilistic approach provides the only reasonable way to understand causation in autoimmune diseases. This conclusion has important implications for other deterministic hypotheses in autoimmunity including other component-cause hypotheses.
Asunto(s)
Enfermedades Autoinmunes/etiología , Predisposición Genética a la Enfermedad , Modelos Biológicos , Enfermedades Autoinmunes/genética , Humanos , Modelos Estadísticos , Medición de Riesgo , Factores de RiesgoRESUMEN
CD4 T-cells have an important role in the autoimmune response in multiple sclerosis (MS). We investigate the possibility that a shift occurs in the T-cell receptor (TR) repertoire of identical twins discordant for MS. We compare the CDR3 spectratype distributions of 24 different TR V beta (TRBV) segments in naïve CD4 T-cells from discordant MS twins and from healthy identical twins. We also compare the CDR3 spectratype distributions in unrelated healthy pairs, formed by combining members of different healthy twins, with the CDR3 spectratype distributions in unrelated pairs of MS patients and in unrelated pairs of their apparently healthy cotwins, formed by combining members of different discordant twins. We use the correlation coefficient (r-value) as a measure of similarity of CDR3 spectratypes in each pair, and we test for the significance of the difference between r-values from the different pairs. We observe that the r-value for the CDR3 spectratype distributions among discordant twins differs significantly from the corresponding r-value for the healthy twins for two TRBV segments. Further, the r-values, for both the unrelated MS patient pairs and the unrelated pairs of their apparently healthy cotwins, differ significantly from the r-values for healthy unrelated pairs of individuals. We conclude that both the MS patients and their apparently healthy cotwins have shifts in their CDR3 repertoires. Because we study naïve CD4 T-cells, we postulate that CDR3 repertoire shifts precede MS and predispose to MS, but are unlikely to be sufficient to cause MS.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Enfermedades en Gemelos , Esclerosis Múltiple/inmunología , Complejo Receptor-CD3 del Antígeno de Linfocito T/análisis , Gemelos Monocigóticos , Adulto , Autorradiografía , Complejo CD3/análisis , Estudios de Casos y Controles , Interpretación Estadística de Datos , Susceptibilidad a Enfermedades/inmunología , Humanos , Inmunofenotipificación , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , Complejo Receptor-CD3 del Antígeno de Linfocito T/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/análisisRESUMEN
BACKGROUND: Utz et al., in a study of identical twins discordant for MS, showed that antigen-stimulated T cells from the MS twins have a major shift in their T-cell receptor (TCR) repertoires when compared with the healthy twins. We hypothesized that a shift in the TCR repertoire precedes the onset of MS and tested this hypothesis by studying unstimulated naive T cells because the TCR repertoires of these cells are largely unaffected by disease. OBJECTIVE: To investigate whether unstimulated naive T cells from MS patients have a detectable shift in their TCR repertoires. METHODS: We analyzed the TCR J beta (TCRBJ) repertoires of naive T cells from identical twin pairs discordant for MS, healthy identical twin pairs, healthy unrelated pairs, and unrelated MS patient pairs. The correlation coefficient (r value) was used as a measure of similarity of TCRBJ repertoires in each pair of individuals. Fisher's z transformation was then used to test for the significance of the difference between the r values from different pairs. RESULTS: The TCRBJ repertoires of the discordant MS twin pairs were significantly different from those of the healthy identical twin pairs, whereas MS patient pairs had TCRBJ repertoires similar to those of the healthy unrelated pairs formed from healthy twin pairs and discordant MS twin pairs. CONCLUSIONS: MS patients have a major shift in their naive T-cell TCRBJ repertoires compared with healthy individuals, implying that this shift precedes the disease onset. This shift could represent the nongenetic factor that explains MS discordance in genetically identical individuals.
Asunto(s)
Esclerosis Múltiple/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Adolescente , Adulto , Enfermedades en Gemelos , Humanos , Persona de Mediana Edad , Esclerosis Múltiple/genética , Receptores de Antígenos de Linfocitos T/genéticaAsunto(s)
Electroforesis en Gel de Agar/métodos , Reacción en Cadena de la Polimerasa/métodos , ARN Mensajero/análisis , Receptores de Antígenos de Linfocitos T alfa-beta/genética , ADN Complementario/genética , Humanos , ARN Mensajero/genética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Factores de TiempoRESUMEN
We analyzed the association of HLA-DR and -DQ haplotypes and alleles with multiple sclerosis (MS) in 91 patients and 91 controls from Iceland using the relative predispositional effect method. The aim was to establish whether there is heterogeneity in HLA associations with MS, whether there are both predispositional and protective haplotypes, and whether sequence motifs also contribute to MS susceptibility. MS was positively associated with a DR2 haplotype (DRB5*0101-DQA1*0102-DQB1*0602), and empirical logistic analysis indicated that this haplotype is MS-associated because of a primary MS association with the DR2 allele. A DR13 haplotype (DRB1*1302-DQA1*0102-DQB1*0604) was negatively associated with MS, i.e., protective. Study of DR2-negative patients and controls confirmed this negative association and identified a second protective DR haplotype (DRB1*0701-DQA1*0201-DQB1*0201). Within these protective haplotypes in DR2-negative individuals, both DQA1 alleles and one DQB1 allele (*0604) were protective, but neither DR allele was protective, i.e., DQ loci may be more important than DR loci in encoding molecules protective against MS. Predispositional (Phe67) and protective (Ile67) DR beta sequence motifs were present in the total and DR2-negative patient and control groups. Since DQ but not DR alleles appear to be protective, DR beta Ile67 may confer additional protection against MS. Study of family-normal controls confirmed the MS association with the DR2 haplotype, and the transmission-disequilibrium test showed cosegregation and linkage of DR2 alleles and MS in families.
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Antígenos de Histocompatibilidad Clase II/genética , Esclerosis Múltiple/genética , Alelos , Estudios de Casos y Controles , Frecuencia de los Genes , Ligamiento Genético , Predisposición Genética a la Enfermedad , Genotipo , Antígenos HLA-DQ/genética , Antígeno HLA-DR2/genética , Haplotipos , Humanos , Islandia , Valores de ReferenciaRESUMEN
The second published case of amyloidoma in the pelvis and sacrum is reported. Fine needle aspiration biopsy revealed multinucleate giant cells, lymphocytes and plasma cells, some atypical. Congo red staining of the cell block and aspirate showed focal, apple-green birefringence consistent with amyloid. The histologic, radiologic and clinical features of this case are discussed, and the cytologic findings in previously reported fine needle aspiration biopsies of amyloidomas are reviewed.
Asunto(s)
Amiloidosis/diagnóstico , Anciano , Amiloide/metabolismo , Amiloidosis/diagnóstico por imagen , Amiloidosis/patología , Biopsia con Aguja , Células Gigantes/patología , Humanos , Linfocitos/patología , Masculino , Células Plasmáticas/patología , Radiografía , Región SacrococcígeaRESUMEN
Twin studies have established that susceptibility to multiple sclerosis (MS) is partly genetic. Attempts to identify the relevant genetic loci have involved population-based studies, to detect associations between a genetic marker and MS, and family studies, to detect linkage between a putative marker and MS. Most of this genetic work is driven by the view that MS is an autoimmune disease. Thus, the focus has been mainly on genes known to be important in the immune response: human leukocyte antigen (HLA) genes, T-cell receptor genes, and immunoglobulin genes. To date, only the particular HLA-DR2 haplotype that is common in Caucasians can be concluded to be important in MS susceptibility in most populations. Studies of other genetic loci have been few, the data obtained often have been conflicting or controversial, and further studies are needed to clarify the biological significance of these loci in MS. Recommendations for further studies are provided in order to overcome some of the problems that have plagued earlier work in MS such as nonreproducibility of results.
Asunto(s)
Esclerosis Múltiple/genética , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Humanos , Polimorfismo Genético , Receptores de Antígenos de Linfocitos T/genética , Estudios en Gemelos como AsuntoRESUMEN
HLA-DR/DQ-DP linkage disequilibrium was investigated in healthy, unrelated British (n = 150) and French Canadian (n = 67) Caucasoid subjects. HLA-DR and DQ typing was performed by Taq I DNA-RFLP analysis, while DPB1 typing was performed by PCR-SSOP. chi 2 and Fisher's exact tests were performed for all 2-locus biallelic comparisons and coefficients of linkage disequilibrium determined. In the British population, only one example of linkage disequilibrium, significant at P = 0.05 (after correction for the number of comparisons made) was seen (DPB1*0101-DRB1*0301[17(1)]). Additional associations, significant at P = 0.05 before correction for the number of comparisons were also seen, including DPB1*0401-DRB1*15, DPB1*1101-DRB1*0701(7(1)), DPB1*1701-DRB1*0701/ 2(7(2)), DPB1*0101-DQA1*0501, DPB1*0401-DQA1*0102, DPB1*0501-DQA1*0102, DPB1*0101-DQB1*0201, DPB1*0401-DQB1*0602/0603 and DPB1*1101-DQB1*0201. With one exception (DPB1*1101-DQB1*0201), none of these associations was seen in the French Canadian group. These results indicate that although more frequent than thought hitherto, HLA class II linkage disequilibrium involving DPB1 alleles is generally weak, and can differ even between different caucasoid populations. This may have implications for HLA and disease studies.
Asunto(s)
Antígenos HLA-DP/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Desequilibrio de Ligamiento , Población Blanca/genética , Alelos , Canadá , Francia/etnología , Frecuencia de los Genes , Prueba de Histocompatibilidad , Humanos , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Reino Unido/etnologíaRESUMEN
Patient sharing of HLA-DQ allelic polymorphisms is a possible explanation for the association of multiple sclerosis (MS) with different HLA class II haplotypes in different populations. We used two-locus linkage analysis to investigate the relevance of three different polymorphisms to MS susceptibility in 79 French Canadian patients and 62 mixed ethnic white patients. In French Canadians, we found that an MS association with shared DQB1 sequences and a DQA1 codon for glutamine at residue 34 is secondary to an MS association with the common DR2 haplotype, DRB1*1501-DQA1*0102-DQB1*0602. In contrast, we found that an MS association in French Canadians with a DQB1 codon for leucine at residue 26 (DQ beta Leu26) is not secondary to an MS association with the DR2-bearing haplotype. Mixed ethnic whites showed a positive MS association with the DR2 haplotype but no MS association with any of these polymorphisms. We conclude that (1) the DR2 haplotype is predispositional for MS in both populations, (2) DQ beta Leu26 is an additional predispositional factor in French Canadians, and (3) none of the DQ polymorphisms fully explains the association of MS with HLA alleles in both patient groups.
Asunto(s)
Genes MHC Clase II/genética , Antígenos HLA-DQ/genética , Esclerosis Múltiple/genética , Polimorfismo Genético , Alelos , Francia/etnología , Ligamiento Genético , Haplotipos , Humanos , Esclerosis Múltiple/etnología , Nueva Escocia , Polimorfismo de Longitud del Fragmento de Restricción , QuebecRESUMEN
We analyzed the association of HLA-DQA1 and -DQB1 alleles with multiple sclerosis (MS) in a collaborative study of 116 Sardinian and 75 French Canadian MS patients by the relative predispositional effect method. In French Canadians, MS was positively associated with DQA1*0102 and DQB1*0602, but there was no positive association of either allele with Sardinian MS, which, by contrast, was positively associated with DQB1*0302 and *0201 and with DQA1*0301, whereas none of these alleles was MS-associated in French Canadians. In comparison with French Canadian results, DQA1*0102 was protective against MS in Sardinians. We suggest that DQA1*0102 has no MS predispositional role in French Canadians, but is MS-associated because it is in linkage disequilibrium with true predispositional alleles present within the DQB1*0602-bearing haplotype. Whereas DQB1 alleles encoding leucine (Leu) at residue 26 showed a strong MS association in French Canadians (relative risk = 24.7), there was no correlation with DQ beta Leu26 in Sardinian MS. No other DQA1 or DQB1 codons showed a positive disease correlation in both groups. Together the data suggest that the two MS patient groups are immunogenetically distinct, and it may be impossible to formulate a unifying hypothesis that explains the different MS-class II associations in these and other ethnic groups.
Asunto(s)
Frecuencia de los Genes , Antígenos HLA-DQ/genética , Esclerosis Múltiple/genética , Alelos , Canadá , Susceptibilidad a Enfermedades , Antígenos HLA-DQ/inmunología , Cadenas alfa de HLA-DQ , Cadenas beta de HLA-DQ , Haplotipos , Humanos , Italia , Esclerosis Múltiple/inmunologíaRESUMEN
Putative disease susceptibility and resistance HLA class II alleles were studied in 78 French Canadian multiple sclerosis (MS) patients and 79 controls by using sequence-specific oligonucleotide probes to analyze in vitro amplified DNA (PCR-SSOP) typing). In this relatively homogeneous ethnic group, MS was positively associated with DRB5*0101, DQB1*0602, and DQA1*0102 and negatively associated with DQB1*0301. The strongest disease association was with DQB1*0602. Complete DQB1 typing of these individuals, plus RFLP DQ beta typing of an additional five patients showed that 98% of patients compared with 73% of controls carry DQB1 alleles encoding leucine at residue 26. In contrast, 16% of patients compared with 38% of controls carry DQB1 alleles encoding tyrosine at the same residue, and 22% of patients versus 44% of controls carry DQB1 alleles encoding glycine at residue 26. The positive disease correlation was confirmed with SSO probes designed to hybridize to codons for amino acids 22-27 of DQB1*0602, 0603, 0604, 0302, 0303 or to codons for amino acids 25-31 of DQB1*0201; all of these alleles encode Leu 26. These findings suggest that DQ beta chain polymorphisms at a single residue contribute to the development of MS in the French Canadian population.
Asunto(s)
Enfermedades Autoinmunes/etnología , Antígenos HLA-DQ/genética , Esclerosis Múltiple/etnología , Alelos , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Secuencia de Bases , Canadá , Susceptibilidad a Enfermedades/inmunología , Etnicidad/genética , Francia/etnología , Frecuencia de los Genes , Genes MHC Clase II , Predisposición Genética a la Enfermedad , Antígenos HLA-DQ/inmunología , Cadenas beta de HLA-DQ , Humanos , Datos de Secuencia Molecular , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Reacción en Cadena de la PolimerasaRESUMEN
Complications of immunosuppression are thought to be rare with the use of low dose pulse methotrexate (MTX) for nonneoplastic conditions. We describe 4 complications of immunosuppression observed in a group of 41 patients who had received MTX for at least 6 months, during a 2-year period. We report the first case of a reversible lymphoproliferative disorder similar to that reported with immunosuppressive therapy associated with organ transplantation. Two cases of disseminated herpes zoster and 1 case with Pneumocystis carinii pneumonia are described. As the indications for the use of low dose MTX broaden and older patients with other comorbid diseases are included, our experience suggests that complications of immunosuppression with prolonged use of MTX may be seen more commonly.
Asunto(s)
Terapia de Inmunosupresión/efectos adversos , Metotrexato/efectos adversos , Anciano , Anciano de 80 o más Años , Artritis Psoriásica/complicaciones , Artritis Psoriásica/tratamiento farmacológico , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Femenino , Herpes Zóster/inducido químicamente , Herpes Zóster/epidemiología , Humanos , Incidencia , Trastornos Linfoproliferativos/inducido químicamente , Trastornos Linfoproliferativos/epidemiología , Metotrexato/uso terapéutico , Persona de Mediana Edad , Neumonía por Pneumocystis/inducido químicamente , Neumonía por Pneumocystis/epidemiologíaRESUMEN
The development of a characteristic ophthalmopathy is a feature of autoimmune diseases of the thyroid. The link between the conditions has not yet been discovered, but here Jack Wall and colleagues develop the theory that an autoimmune response to a 64 kDa antigen expressed on both thyroid and eye muscle membranes is responsible for this thyroid-associated ophthalmopathy.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedad de Graves/inmunología , Tiroiditis Autoinmune/inmunología , Autoantígenos/inmunología , Reacciones Cruzadas/inmunología , Humanos , Modelos Biológicos , Músculos Oculomotores/inmunología , Órbita/inmunología , Glándula Tiroides/inmunologíaRESUMEN
HLA-DPB1 typing was performed using polymerase chain reaction DNA amplification and sequence-specific oligonucleotide probing (PCR-SSOP) which permitted identification of 17 distinct DPB alleles using 15 oligonucleotide probes. The accuracy of this approach was confirmed in an initial study of 26 human B-lymphoblastoid cell lines which demonstrated close agreement between PCR-SSOP and PLT assigned types. A cohort of 47 adult French Canadians was then studied to provide an estimate of DPB1 allelic frequencies in an ethnically homogeneous population. DPB1*0401 was the most frequent phenotype (61.5%) and only DPB1*0101, 0301 and 0402 were also present at frequencies greater than 10%. HLA-DPw4 has been reported to be associated with multiple sclerosis (MS) but our PCR-SSOP analysis of 52 French Canadian MS patients showed no association with either the DPB1*0401 or DPB1*0402 splits of DPw4 or with any other DPB1 allele.