RESUMO
Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.
Assuntos
Neoplasias do Sistema Nervoso Central/etiologia , Neoplasias do Sistema Nervoso Central/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Linfoma/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/virologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/isolamento & purificação , Humanos , Tolerância Imunológica , Linfoma/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Transcriptoma , Microambiente TumoralRESUMO
In diffuse large B-cell lymphoma (DLBCL), the clinical and biological significance of concordant and discordant bone marrow (BM) involvement have not been well investigated. We evaluated 712 de novo DLBCL patients with front-line rituximab-containing treatment, including 263 patients with positive and 449 with negative BM status. Compared with negative BM disease, concordant BM adversely impacted overall and progression-free survival, independent of the International Prognostic Index (IPI) and cell-of-origin classification. Once BM is concordantly involved, poor prognosis was not associated with the extent of BM involvement. Conversely, patients with discordant BM showed favorable overall survival similar to stage I-II DLBCL. A BM-adjusted IPI, using three parameters: concordant BM involvement, age >60 years, and performance status >1, improves the risk stratification for DLBCL with positive BM. Intensive immunochemotherapy seemingly rendered survival benefit for patients with concordant BM, as did rituximab maintenance for the discordant BM group. Frequently revealing adverse clinical and molecular characteristics, patients with concordant BM demonstrated gene expression signatures relevant to tumor cell proliferation, migration and immune escape. In conclusion, clinical and biological heterogeneity is seen in DLBCL with positive BM but concordant BM involvement represents a distinct subset with unfavorable gene signatures, high-risk clinicopathologic features and poor prognosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Medula Óssea/patologia , Intervalo Livre de Doença , Feminino , Humanos , Fatores Imunológicos/metabolismo , Imunoterapia/métodos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBCL was effectively evaluated for PRDM1/BLIMP-1 deletion, mutation, and protein expression. BLIMP-1 expression was frequently associated with the ABC phenotype and plasmablastic morphologic subtype of DLBCL, yet 63% of the ABC-DLBCL patients were negative for BLIMP-1 protein expression. In these patients, loss of BLIMP-1 was associated with Myc overexpression and decreased expression of p53 pathway molecules. In addition, homozygous PRDM1 deletions and PRDM1 mutations within exons 1 and 2, which encode for domains crucial for transcriptional repression, were found to show a poor prognostic impact in patients with ABC-DLBCL but not in those with germinal center B-cell-like DLBCL (GCB-DLBCL). Gene expression profiling revealed that loss of PRDM1/BLIMP-1 expression correlated with a decreased plasma-cell differentiation signature and upregulation of genes involved in B-cell receptor signaling and tumor-cell proliferation. In conclusion, these results provide novel clinical and biological insight into the tumor-suppressive role of PRDM1/BLIMP-1 in ABC-DLBCL patients and suggest that loss of PRDM1/BLIMP-1 function contributes to the overall poor prognosis of ABC-DLBCL patients.
Assuntos
Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Mutação , Proteínas Repressoras/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Biópsia , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fator 1 de Ligação ao Domínio I Regulador Positivo , Prognóstico , Proteínas Repressoras/metabolismo , Deleção de Sequência , Transcriptoma , Resultado do Tratamento , Adulto JovemRESUMO
Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of ß-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast-activated ß-catenin in HSCs. Moreover, using cell-specific gene inactivation mouse models, we show that FoxO1 expression in osteoblasts is required for and mediates the leukemogenic properties of ß-catenin. At the molecular level, FoxO1 interacts with ß-catenin in osteoblasts to induce expression of the Notch ligand, Jagged-1. Subsequent activation of Notch signaling in long-term repopulating HSC progenitors induces the leukemogenic transformation of HSCs and ultimately leads to the development of AML. These findings identify FoxO1 expressed in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/activated ß-catenin interaction results in AML. These observations support the notion that the bone marrow niche is an instigator of leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues.
Assuntos
Fatores de Transcrição Forkhead/fisiologia , Leucemia Mieloide Aguda/etiologia , Osteoblastos/fisiologia , beta Catenina/fisiologia , Anemia/etiologia , Animais , Proteínas de Ligação ao Cálcio/genética , Proteína Forkhead Box O1 , Células-Tronco Hematopoéticas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína Jagged-1 , Proteínas de Membrana/genética , Camundongos , Receptores Notch/fisiologia , Proteínas Serrate-Jagged , Transdução de SinaisRESUMO
Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease with marked genomic instability and variable response to conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. More clinically aggressive cases of DLBCLs have high level of circulating interleukin 10 (IL10) cytokine and evidence of activated intracellular STAT3 (signal transducer and activator of transcription 3) signaling. We investigated the role of IL10 and its surface receptor in supporting the neoplastic phenotype of DLBCLs. We determined that IL10RA gene is amplified in 21% and IL10RB gene in 10% of primary DLBCLs. Gene expression of IL10, IL10RA and IL10RB was markedly elevated in DLBCLs. We hypothesized that DLBCLs depend for their proliferation and survival on IL10-STAT3 signaling and that blocking the IL10 receptor (IL10R) would induce cell death. We used anti-IL10R blocking antibody, which resulted in a dose-dependent cell death in all tested activated B-cell-like subtype of DLBCL cell lines and primary DLBCLs. Response of germinal center B-cell-like subtype of DLBCL cell lines to anti-IL10R antibody varied from sensitive to resistant. Cells underwent cell cycle arrest, followed by induction of apoptosis. Cell death depended on inhibition of STAT3 and, to a lesser extent, STAT1 signaling. Anti-IL10R treatment resulted in interruption of IL10-IL10R autostimulatory loop. We thus propose that IL10R is a novel therapeutic target in DLBCLs.
Assuntos
Biomarcadores Tumorais/metabolismo , Interleucina-10/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Receptores de Interleucina-10/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Western Blotting , Ciclo Celular , Proliferação de Células , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Técnicas Imunoenzimáticas , Interleucina-10/genética , Linfoma Difuso de Grandes Células B/mortalidade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina-10/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Análise Serial de Tecidos , Células Tumorais CultivadasRESUMO
Ataxia telangiectasia-mutated (ATM) kinase is a master regulator of the DNA damage response. ATM is frequently inactivated in human B-cell non-Hodgkin lymphomas, including ~50% of mantle cell lymphomas (MCLs) characterized by ectopic expression of CyclinD1. Here we report that early and robust deletion of ATM in precursor/progenitor B cells causes cell autonomous, clonal mature B-cell lymphomas of both pre- and post-germinal center (GC) origins. Unexpectedly, naive B-cell-specific deletion of ATM is not sufficient to induce lymphomas in mice, highlighting the important tumor suppressor function of ATM in immature B cells. Although EµCyclinD1 is not sufficient to induce lymphomas, EµCyclinD1 accelerates the kinetics and increases the incidence of clonal lymphomas in ATM-deficient B-cells and skews the lymphomas toward pre-GC-derived small lymphocytic neoplasms, sharing morphological features of human MCL. This is in part due to CyclinD1-driven expansion of ATM-deficient naive B cells with genomic instability, which promotes the deletions of additional tumor suppressor genes (i.e. Trp53, Mll2, Rb1 and Cdkn2a). Together these findings define a synergistic function of ATM and CyclinD1 in pre-GC B-cell proliferation and lymphomagenesis and provide a prototypic animal model to study the pathogenesis of human MCL.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/fisiologia , Linfócitos B/patologia , Ciclina D1/metabolismo , Centro Germinativo/patologia , Linfoma de Células B/patologia , Linfopenia/patologia , Animais , Linfócitos B/metabolismo , Southern Blotting , Western Blotting , Proliferação de Células , Ciclina D1/genética , Citometria de Fluxo , Instabilidade Genômica , Centro Germinativo/metabolismo , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma de Células B/mortalidade , Linfopenia/genética , Linfopenia/metabolismo , Linfopenia/mortalidade , Camundongos , Células Tumorais CultivadasRESUMO
BACKGROUND: High levels of cyclin E (CCNE) are accompanied by shorter survival in cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP)-treated diffuse large B-cell lymphomas (DLBCL), independent of the international prognostic index (IPI). Data on the prognostic role of CCNE in the 'rituximab (R)-era' are lacking. METHODS: To test reproducibility and applicability of observations from the 'pre-R era' to the 'R era', we examined the prognostic role of CCNE expression by immunohistochemistry in 1579 DLBCL on tissue microarrays (TMA); 339 patients were treated by CHOP and 635 by R-CHOP. RESULTS: 1209 samples (77%) were evaluable; failures were due to missing TMA punches and fixation artefacts. Mean expression of CCNE was 13% (0-85%); applying a cut-off of >16%, 382 DLBCL (31%) were positive. CCNE did not correlate with any of the known variables (IPI, primary site, cell of origin, proliferation, and BCL2- or C-MYC rearrangements). We were able to reproduce data suggesting an IPI- and response to therapy independent, negative prognostic impact of CCNE in CHOP-treated DLBCL patients: CCNE-positive cases had a median survival of 16 months compared with 57 months in negative ones (p=0.012). In R-CHOP-treated patients the prognostic impact of CCNE was abrogated and only IPI, cell of origin and response to therapy had a prognostic significance. CONCLUSIONS: Addition of R to CHOP overcomes the negative prognostic impact of CCNE in DLBCL. Thus, R not only prolongs survival in DLBCL but also serves a cautionary note that prognostic factors should not be transferred into the 'R era' without proper scientific studies.
Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclina E/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Oncogênicas/metabolismo , Idoso , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Reprodutibilidade dos Testes , Rituximab , Análise Serial de Tecidos , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development-namely germinal center B-cell like and activated B-cell like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1 and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B cells. Cutoffs for each marker were obtained using receiver-operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1 and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy.
Assuntos
Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Anticorpos Monoclonais Murinos/administração & dosagem , Biomarcadores Tumorais/metabolismo , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Técnicas Imunoenzimáticas , Imunofenotipagem , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prednisona/administração & dosagem , Prognóstico , Rituximab , Taxa de Sobrevida , Análise Serial de Tecidos , Vincristina/administração & dosagemRESUMO
BACKGROUND: Endoscopy and biopsy are used to diagnose coeliac disease. There are, however, observer-dependent interpretations of the degree of villous atrophy in biopsies. A pilot study using quantitative image-processing procedures was performed to quantify the degree of villous atrophy in patients with coeliac disease. METHOD: The degree of villous atrophy in duodenal biopsy images was quantified by calculating the ratio of villous edge-to-piecewise arc length (E/P ratio), and this value was compared with the blinded assessment of Marsh score for degree of villous atrophy. RESULTS: Mean E/P ratios for n = 31 biopsy images, 2.76 (SD 0.44) (Marsh IIIa), 1.91 (0.50) (Marsh IIIb) and 1.18 (0.22) (Marsh IIIc), were significantly different (p = 0.006). Based on non-parametric testing, the E/P ratios were inversely correlated with Marsh scores (Spearman coefficient rho = -0.798, Kendall tau = -0.681; p<0.0001). CONCLUSIONS: Biopsy images quantified by image analysis correlated exceedingly well with the histopathological grade of villous atrophy. Since quantified measurements are real-numbered values and lack observer bias, measurement of villous atrophy based on image analysis lends itself to standardisation of histological grading.
Assuntos
Doença Celíaca/patologia , Duodeno/patologia , Processamento de Imagem Assistida por Computador , Mucosa Intestinal/patologia , Atrofia , Duodeno/ultraestrutura , Humanos , Mucosa Intestinal/ultraestrutura , Microvilosidades/patologia , Projetos PilotoRESUMO
BACKGROUND: Chronic pancreatitis is a known risk factor for pancreatic adenocarcinoma. Recent work has pointed to a role for bone marrow-derived progenitor cells (BMDCs) in chronic inflammation-based carcinogenesis. Consequently, the role of BMDCs in chronic pancreatitis was investigated. METHODS: The fate of BMDCs was followed using green fluorescent protein and the Y chromosome as bone marrow markers in gender-mismatched transplanted mice treated with repeated injections of cerulein for up to 45 weeks. The phenotype of engrafted BMDCs was assessed based on the co-expression of bone marrow and pancreatic markers. RESULTS: After 45 weeks of cerulein treatment, mice developed severe chronic pancreatitis but no preneoplastic lesions. BMDCs did engraft in the pancreas. Most of the BMDCs were desmin positive and contributed to 5.12% (1.12%) (mean (SEM)) of the pancreatic stellate cell population. Pancreatic stellate cells derived from the bone marrow could be activated, as demonstrated by alpha-smooth muscle actin expression, suggesting a role in tissue repair. BMDCs could also be found in pancreatic ducts, based on dolichos biflorus agglutinin and cytokeratin 19 stainings, but at a much lower frequency (0.62% (0.11%)). CONCLUSION: BMDCs contribute to the pancreatic stellate cell population, suggesting a role in pancreatic tissue repair. In the absence of preneoplastic lesions, BMDCs contribute at a very low level to the ductal epithelium of the chronically inflamed pancreas. The role of BMDCs in pancreatic carcinogenesis remains to be defined.
Assuntos
Células da Medula Óssea/patologia , Proteínas de Fluorescência Verde , Pancreatite Crônica/patologia , Células-Tronco/patologia , Animais , Transplante de Medula Óssea , Ceruletídeo , Modelos Animais de Doenças , Técnicas Imunoenzimáticas , Hibridização In Situ , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Pancreatite Crônica/induzido quimicamente , Cromossomo YRESUMO
BACKGROUND AND STUDY AIMS: In patients with Barrett's esophagus (BE), targeted endoscopic mucosal resection (EMR) of visible lesions of high grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) is effective, but carries the risk of leaving in place synchronous lesions and Barrett's epithelium with the potential for recurrent disease. We evaluated the safety and long-term efficacy of complete Barrett's eradication EMR (CBE-EMR) for the treatment of patients with HGD or IMC, independently of the presence of macroscopically visible lesions or surgical risk. PATIENTS AND METHODS: 26 consecutive patients with BE and HGD or IMC underwent CBE-EMRs, which were performed with the endoscopic cap suction method and/or a 2.3-mm monofilament mucosectomy snare. Endoscopic follow up after completion of resection was carried out to assess the rate of residual or recurrent BE with or without HGD or IMC. RESULTS: 24 patients completed the study. They underwent a total of 44 EMR sessions with a median of 3 pieces (range 1-8) removed per session. Two patients with immediate bleeding were successfully managed endoscopically. Three patients developed an early esophageal stricture that was completely resolved with a single endoscopic dilation. After a median follow-up of 28 months (range 15-51 months), persistent endoscopic and histologic eradication of BE was demonstrated in 21 patients (87.5 %). In two patients, Barrett's epithelium was detected beneath the neosquamous epithelium 3 months after completion of the resection. In the remaining patient, IMC was found in a nodule seen and removed by EMR at 12-month surveillance endoscopy. CONCLUSIONS: CBE-EMR is a safe and highly effective long-term treatment that should be offered to all patients with Barrett's esophagus with HGD and IMC.
Assuntos
Adenocarcinoma/cirurgia , Carcinoma/cirurgia , Neoplasias Esofágicas/cirurgia , Esofagoscopia/métodos , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/mortalidade , Esôfago de Barrett/patologia , Esôfago de Barrett/cirurgia , Carcinoma/mortalidade , Carcinoma/patologia , Neoplasias Esofágicas/patologia , Esofagectomia/métodos , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Mucosa/patologia , Mucosa/cirurgia , Estadiamento de Neoplasias , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoAssuntos
Crioglobulinemia/diagnóstico , Glomerulonefrite/diagnóstico , Leucemia Linfocítica Crônica de Células B/complicações , Crioglobulinemia/etiologia , Crioglobulinemia/patologia , Feminino , Glomerulonefrite/etiologia , Glomerulonefrite/patologia , Humanos , Rim/patologia , Pessoa de Meia-IdadeRESUMO
An increased incidence of acute myeloid leukemia (AML) has recently been documented in patients post-solid organ transplantation but the incidence and types of myelodysplastic syndromes (MDS) occurring in this patient population are not known. We identified 5 patients (3M, 2F, age 48-64 years) who developed MDS ranging from 1.8 to 25 years (median 4.2 years) post-solid organ transplantation, only 2 patients had received azathioprine. The cumulative incidence of MDS in heart and lung transplant recipients at 15 years was 0.5% and 1.8%, respectively, which is markedly higher compared to the general population. Low-risk types of MDS predominated, 3 of 5 patients are alive (median 3.9 years) since diagnosis. Deletions of chromosome 20q, which have not been previously reported in post-transplant MDS/AML, were identified in 3 cases. Our findings expand the morphologic and cytogenetic spectrum of MDS occurring post-solid organ transplantation and suggest that mechanisms beside azathioprine toxicity might be important in disease pathogenesis.
Assuntos
Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/epidemiologia , Transplante de Órgãos/efeitos adversos , Biópsia , Medula Óssea/patologia , Feminino , Humanos , Incidência , Leucemia Mieloide/epidemiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Transplante de Órgãos/classificação , Complicações Pós-Operatórias/classificação , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/patologia , Estudos RetrospectivosRESUMO
BACKGROUND AND AIM: Both the clinical presentation and the degree of mucosal damage in coeliac disease vary greatly. In view of conflicting information as to whether the mode of presentation correlates with the degree of villous atrophy, we reviewed a large cohort of patients with coeliac disease. PATIENTS AND METHODS: We correlated mode of presentation (classical, diarrhoea predominant or atypical/silent) with histology of duodenal biopsies and examined their trends over time. RESULTS: The cohort consisted of 499 adults, mean age 44.1 years, 68% females. The majority had silent coeliac disease (56%) and total villous atrophy (65%). There was no correlation of mode of presentation with the degree of villous atrophy (p=0.25). Sixty-eight percent of females and 58% of males had a severe villous atrophy (p=0.052). There was a significant trend over time for a greater proportion of patients presenting as atypical/silent coeliac disease and having partial villous atrophy, though the majority still had total villous atrophy. CONCLUSIONS: Among our patients the degree of villous atrophy in duodenal biopsies did not correlate with the mode of presentation, indicating that factors other than the degree of villous atrophy must account for diarrhoea in coeliac disease.
Assuntos
Doença Celíaca/patologia , Duodeno/patologia , Mucosa Intestinal/patologia , Adulto , Atrofia/patologia , Biópsia , Estudos de Coortes , Duodeno/cirurgia , Feminino , Humanos , Masculino , Microvilosidades/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de DoençaAssuntos
Antineoplásicos/uso terapêutico , Deleção de Genes , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Tretinoína/uso terapêutico , Adolescente , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Leucemia Promielocítica Aguda/genética , Masculino , Pessoa de Meia-IdadeRESUMO
This study reports the first well-documented case of sporadic Burkitt lymphoma arising in and confined to the uterine corpus in a 40-year-old woman who presented with vaginal bleeding. Endometrial curettings showed a diffuse infiltrate of medium sized lymphocytes with the characteristic morphologic and immunophenotypic features of Burkitt lymphoma. Fluorescence in-situ hybridization demonstrated the t(8;14)(q24;q32) translocation. There was no evidence of extra-uterine disease and the patient is alive without disease 10 months after hysterectomy and chemotherapy. This report demonstrates that Burkitt lymphoma can present as isolated, organ confined disease at unusual sites and with protean symptoms.
Assuntos
Linfoma de Burkitt/patologia , Neoplasias Uterinas/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/genética , Linfoma de Burkitt/terapia , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Histerectomia , Hibridização in Situ Fluorescente/métodos , Sensibilidade e Especificidade , Translocação Genética , Resultado do Tratamento , Neoplasias Uterinas/genética , Neoplasias Uterinas/terapiaRESUMO
OBJECTIVE: This study compares vascular closure staples (VCSs) with conventional sutures in the rabbit carotid vein graft model to determine whether anastomotic technique affects cellular proliferation, blood velocity, or intimal changes when measured over a period of 3 months postoperatively. METHODS: Twenty-six New Zealand White rabbits weighing 3.0-3.2 kg underwent interposition of jugular vein grafts in left carotid arteries. Half of the animals had anastomoses performed with small VCSs (n = 13) and half had anastomoses performed with 8-O interrupted polypropylene suture. Animals were allowed to survive for 1 week (n = 4, VCS; n = 4, suture), 2 weeks (n = 4, VCS; n = 4, suture), and 3 months (n = 5, VCS; n = 5, suture). The peak systolic velocity (PSV) at the distal anastomosis was measured after completion of the graft and again at sacrifice in the 3-month survival groups. At sacrifice, sections were taken from the middle and distal end of the vein graft and the distal carotid artery. Vascular cell proliferation was measured using 5-bromo-2'-deoxyuridine labeling and intimal changes were measured using digitized microscopic images. RESULTS: All 26 grafts were open at the time of sacrifice. PSV at the distal clipped anastomosis was 40.52 cm/s (t = 0) and 34.3 cm/s (t = 3 months, P = 0.31). PSV at the distal sutured anastomosis was 38.30 cm/s (t = 0) and 39.23 cm/s (t = 3 months, P = 0.82). There was no difference between the two techniques at either t = 0 or t = 3 months (P = 0.51 and P = 0.31, respectively). Endothelial cell proliferation and smooth muscle cell proliferation at the anastomosis was highest during the 2 weeks after the procedure, then returned to baseline levels by 3 months. But there was no significant difference between the clipped and sutured groups with respect to vascular cell proliferation postoperatively. The intimal thickness changed significantly in the vein graft at the anastomosis for both the clipped and sutured groups (P = 0.0007 and P = 0.002). But there was no difference when the intimal changes for each technique were compared (P = 0.94). CONCLUSION: No differences were observed when peak systolic velocity, vascular cell proliferation, and intimal changes were compared between sutured and stapled anastomoses in rabbit vein interposition grafts over a period of 3 months after surgery.
Assuntos
Anastomose Cirúrgica , Artérias Carótidas/cirurgia , Instrumentos Cirúrgicos , Veias/transplante , Animais , Velocidade do Fluxo Sanguíneo , Trombose das Artérias Carótidas/patologia , Trombose das Artérias Carótidas/cirurgia , Divisão Celular , Endotélio Vascular/patologia , Oclusão de Enxerto Vascular , Hiperplasia , Músculo Liso Vascular/patologia , Complicações Pós-Operatórias/patologia , Coelhos , Suturas , Túnica Íntima/patologia , Veias/patologiaRESUMO
A case of Von Hippel-Lindau's disease lacking the classical Lindau's tumour is reported. The uncommon features of this case are highlighted and the relevant literature is briefly outlined.