RESUMO
A man aged 60 years was examined for intense inflammatory response, night sweats, subfebrile and later febrile temperatures and a weight loss of 18 kg in 7 months. CRP was 270 mg / l, i.e. more than 20 times the upper limit of the physiological range. Reactive leukocytosis (10 × 109/l), thrombocytosis (530 × 109/l), increased fibrinogen (greater than 7 g/l), and anemia with hemoglobin of 80 g/l were present. No infection or systemic autoimmune disease has been proven. The patient had normal renal function and had no osteolytic deposits detectable by FDG-PET/CT. The procalcitonin level was not elevated. The bone marrow examination revealed a 30-40% infiltration of proplasmacyte type with admixture of plasmablasts, expressing light chains λ. Monoclonal immunoglobulin IgA λ was at a low concentration of about 8 g/l and the ratio of free light chains κ/λ was 0.13. The extent of bone marrow infiltration and anemia met the criteria for the diagnosis of symptomatic multiple myeloma. Following initiation of the combination therapy using thalidomide, bortezomib and dexamethasone, the maximum decrease in the concentrations of monoclonal immunoglobulin, free light chains and CRP was observed already after the first 2 cycles of treatment. Later, during the following two 2 cycles, the disease began to progress again. The patient underwent successful stem cell collection after the application of cyclophosphamide 2.5 g/m 2 and leukocyte growth factor (G-CSF), and high-dose chemotherapy (melphalan 200 mg/m 2) with the support of stem cell transplantation. At 2 months following high-dose chemotherapy, CRP levels of the physiological range decreased, the blood count was normalized, and monoclonal immunoglobulin was not detectable. Conclusion: The chronic inflammatory response may be due to plasmocytary bone marrow infiltration even if there are no other symptoms of multiple myel-oma present, except for anemia which, however, also involves the inflammatory reaction. In this case, the systemic inflammatory reaction with high CRP levels signalled aggressive behaviour of the disease. Key words: CRP - multiple myeloma - procalcitonin - systemic inflammatory response.
Assuntos
Mieloma Múltiplo , Síndrome de Resposta Inflamatória Sistêmica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Talidomida/administração & dosagemRESUMO
Common variable immunodeficiency disorder belongs to the most common primary human immunodeficiencies and it is characterized by primary defective immunoglobulin production. Hypogammaglobulinemia manifests in every age, usually in adult people. There is no gender predisposition. The prevalence is 1 : 25 000-1 : 50 000. The ethiopathogenesis of the majority of CVIDs is unknown. The main clinical respiratory symptoms include recurrent respiratory infects, especially bacterial etiology, sinusitis, bronchitis, pneumonia, leading to bronchiectasis and lung fibrosis. Interstitial lung fibrosis and granulomatosis often manifest at diagnosis of CVID and they are negative prognostic factors of the disease.
Assuntos
Agamaglobulinemia/etiologia , Bronquiectasia/etiologia , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Pneumonia/etiologia , Adulto , Imunodeficiência de Variável Comum/epidemiologia , Feminino , Humanos , Masculino , PrevalênciaRESUMO
Rapid differential diagnostics of pulmonary infiltrates suspected of invasive fungal disease in an immunocompromised host and early initiation of effective antifungal therapy are crucial for patient outcomes. There are no serological tests available to detect mucormycetes; therefore, PCR-based methods are highly suitable. We validated our previously published PCR followed by high-resolution melt analysis (PCR/HRMA) to detect Rhizopus spp., Rhizomucor pusillus, Lichtheimia corymbifera, and Mucor spp. in bronchoalveolar lavage (BAL) samples from immunocompromised patients who were at risk of invasive fungal disease. All PCR/HRMA-positive samples were retested using novel real-time quantitative PCR (RQ PCR) assays specific to the species identified. In total, between January 2009 and December 2012 we analyzed 99 BAL samples from 86 patients with pulmonary abnormalities using PCR/HRMA. Ninety (91%) BAL samples were negative, and 9 (9%) samples were positive. The sensitivity and specificity of PCR/HRMA were 100% and 93%, respectively. By combining the positive results of PCR/HRMA with positive RQ PCR results, the specificity was raised to 98%. PCR/HRMA, due to its high negative predictive value (99%), represents a fast and reliable tool for routine BAL sample screening for the differential diagnosis of pulmonary infiltrates in immunocompromised patients for the four most clinically important mucormycetes.
Assuntos
Líquido da Lavagem Broncoalveolar/microbiologia , Pneumopatias Fúngicas/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Mucorales/classificação , Mucorales/isolamento & purificação , Mucormicose/diagnóstico , Reação em Cadeia da Polimerase/métodos , Feminino , Humanos , Hospedeiro Imunocomprometido , Pneumopatias Fúngicas/microbiologia , Masculino , Mucormicose/microbiologia , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Fatores de Tempo , Temperatura de TransiçãoRESUMO
BACKGROUND: Adult Langerhans cell histiocytosis is a rare disorder with diverse clinical manifestations and inconsistent treatment outcomes to conventional therapeutic regimens. Cladribine (2-chlorodeoxyadenosine) repeatedly proved effective in cases of relapsed multifocal and multisystem disease forms. In this retrospective study we present an analysis of cladribine in frontline systemic therapy. MATERIAL AND METHODS: A cohort of seven male patients with biopsy proved multisystem (six cases) and multifocal (one case) Langerhans cell histiocytosis received cladribine at a dose of 5 mg/m(2) subcutaneously (five cases) or by two-hour intravenous infusion (two cases) over five consecutive days, every four weeks for a median of four courses (range 4-6). The treatment was enhanced with cyclophosphamide (300 mg intravenously on days 1-5 in cycles 4-6) and corticoids (dexamethasone 24 mg orally or methylprednisolone 250 mg intravenously on days 1-5 in cycles 4-6) in two patients, with radiotherapy (20 Gy on skin or bone lesions) in three patients and with photochemotherapy (psoralen plus ultraviolet A light, PUVA) on skin lesions in one patient. RESULTS: All patients achieved clinically relevant treatment response confirmed by positron emission tomography (PET). Durable complete remissions were maintained in six patients (86%), including two patients with hypophysis involvement, with the median follow-up of 37 months (range 15-94; 49.8 ± 35.2 [ 6 ]). One patient had an aggressive, early relapsing disease requiring further treatment lines. The treatment-related toxicities consisted of transient bone marrow suppression affecting the leukocytes predominantly. Grade 3 lymphopenia occurred in five patients (71%) and grade 3 neutropenia in one patient (14%). CONCLUSION: Cladribine, both as a single agent as well as in combination with an alkylating cytostatic and corticoids, represents an effective treatment option with favorable toxicity profile for adult patients with multisystem or aggressive multifocal form of Langerhans cell histiocytosis.
Assuntos
Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Histiocitose de Células de Langerhans/tratamento farmacológico , Fotoquimioterapia , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Estudos de Coortes , Terapia Combinada , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Glucocorticoides/uso terapêutico , Histiocitose de Células de Langerhans/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Adulto JovemRESUMO
The case of an HIV-positive man treated for acute toxoplasmosis with no traces of malignancy is reported. A second lymph node extirpation was performed after 5 months, which identified the presence of Hodgkin and Reed-Sternberg (HRS) cells. This case suggests that toxoplasmosis may cause changes in the regulation of surrounding cells and induce neoplastic proliferation.
Assuntos
Doença de Hodgkin/parasitologia , Toxoplasmose/complicações , Adulto , Infecções por HIV/complicações , Infecções por HIV/parasitologia , Infecções por HIV/patologia , Doença de Hodgkin/patologia , Doença de Hodgkin/virologia , Humanos , Masculino , Células de Reed-Sternberg/citologia , Toxoplasmose/patologia , Toxoplasmose/virologiaRESUMO
BACKGROUND/AIMS: Urokinase (uPA) is a serine protease, which together with uPAR, tPA, PAI 1 and PAI 2 forms the plasminogen activator system, a component of metastatic cascade contributing to the invasive growth and angiogenesis of malignant tumours. METHODOLOGY: Both preceding therapy and after 6-8 weeks of the treatment, plasma PAI 1 levels (photometric microplate method on the ELISA) and uPA, uPAR, PAI 1 and PAI 2 tissue expression (immunohistochemical reaction) were analysed from 80 colorectal carcinoma patients. RESULTS: Analysis showed higher pre-treatment plasma levels of PAI 1 in patients with advanced tumours, which decreased after surgery or the start of therapy (p=0.004); Patients with higher plasma level PAI 1 before (0.013) and after therapy (0.004) had significantly shorter survival. There was a higher expression of uPA (p<0.001), uPAR (p<0.001), PAI 1 (p=0.042) and PAI 2 (p<0.001) in advanced colorectal carcinoma. A relationship between PAI 2 (p=0.010) and uPAR (p=0.019) expression and survival was demonstrated. There is a correlation between pre-treatment plasma PAI 1 levels and PAI 2 (p=0.028) and uPAR (p=0.043) expression. CONCLUSIONS: Immunohistochemical analysis of PAS in tumour tissue and plasma PAI 1 levels was found to be a useful prognostic factor in colorectal carcinoma patients. Plasma PAI 1 could be advantageous in evaluating the effectiveness of a mode of treatment.
Assuntos
Neoplasias Colorretais/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Inibidor 2 de Ativador de Plasminogênio/análise , Receptores de Ativador de Plasminogênio Tipo Uroquinase/análise , Ativador de Plasminogênio Tipo Uroquinase/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/análiseRESUMO
We present a method for rapid and simple detection of clinically relevant mucormycetes of the Mucorales order in cultures and clinical samples. This seminested real-time PCR uses mucormycete-specific primers and is followed by species identification using high-resolution melt (HRM) analysis. The method is highly suitable for routine clinical diagnostics.
Assuntos
DNA Fúngico/genética , Mucorales/classificação , Mucorales/isolamento & purificação , Mucormicose/diagnóstico , Micologia/métodos , Reação em Cadeia da Polimerase/métodos , DNA Fúngico/química , Humanos , Dados de Sequência Molecular , Mucorales/genética , Análise de Sequência de DNA , Temperatura de TransiçãoRESUMO
Kaposi's sarcoma (KS) is an unusual form of tumor which in the era of HIV/AIDS pandemic is increasingly observed outside the original endemic areas. It was shown that the development of KS is in directly related to infection with human herpes virus 8 (HHV-8). The pathophysiology of KS is complex and is influenced by HIV co-infection and by global cytokine interactions. Skin, gastrointestinal tract and respiratory organs are typically involved. A good therapeutic effect of combined antiretroviral therapy (cART) was documented. We provode a review of the current knowledge of the pathophysiology of and therapeutic options for KS and one clinical case.
Assuntos
Sarcoma de Kaposi , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/terapia , Sarcoma de Kaposi/virologiaRESUMO
Mantle cell lymphoma (MCL) is characterized by the hallmark t(11;14)(q13;q32) translocation, leading to cyclin D1 over-expression. Additionally, disrupting the DNA damage response pathway through ATM or TP53 defects plays an important role in MCL pathogenesis. Using deep next-generation sequencing we analyzed the mutual composition of ATM and TP53 mutations in 72 MCL patients, and assessed their impact on progression-free survival (PFS) and overall survival (OS). Mutated ATM and TP53 alleles were found in 51% (37/72) and 22% (16/72) of the cases examined, respectively, with only three patients harboring mutations in both genes. Only a mutated TP53 gene was associated with the significantly reduced PFS and OS and the same output was observed when ATM and TP53 defective groups included also sole deletions 11q and 17p, respectively. Determining the exact ATM/p53 pathway dysfunction may influence the selection of MCL patients for innovative therapies based on the targeted inhibition of selected proteins.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Predisposição Genética para Doença , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Mutação , Proteína Supressora de Tumor p53/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores Tumorais , Feminino , Estudos de Associação Genética , Humanos , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Masculino , Prognóstico , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Deleção de Sequência , Proteína Supressora de Tumor p53/metabolismoRESUMO
Burkitt's lymphomas (BL) are aggressive rapidly growing tumors typified by a high c-myc expression resulting from t(8;14)(q24;q32), t(2;8)(p12;q24) or t(8;22)(q24;q11) translocations. Alterations of the p53 tumor suppressor are also relatively frequent in BL. Several approaches have been adopted for detection of the p53 aberrations such as immunohistochemical analyses, immunoblotting, DNA sequencing, fluorescence in situ hybridization (FISH), and functional assays. We used these methods to characterize the p53 mutation in tumor cells of a 53-year-old male suffering from Burkitt's lymphoma. By immunohistochemical analyses, we detected high levels of the p53 protein in the tumor tissue. Immunoblotting showed a higher molecular weight of the p53 protein overexpressed in the tumor tissues than that of the standard p53 protein. Similarly, the molecular weight of the PCR product prepared by amplification of the tumor p53 cDNA was higher than that of the standard p53 cDNA. Functional analyses of separated alleles in yeast evidently revealed that the tumor p53 protein was transcriptionally non-functional. The yeast colonies expressing this p53 variant possessed a unique phenotype in that they were red with many white spots on their surface. Sequencing of the tumor cDNA revealed a duplication of the 30 bp region of the p53 gene (g.12155_12184dup30) leading to a repeat of 10 amino acids (Pro-77 to Ala-86) in the p53 protein. Further analyses showed that the mutation was unstable in yeast cells. The FISH analyses did not confer loss of the p53-specific locus 17p13.
Assuntos
Linfoma de Burkitt/genética , Duplicação Gênica , Genes p53 , Mutação , DNA Complementar/química , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor p53/análiseRESUMO
Mutations and deletions of the tumor suppressor TP53 gene are the most frequent genetic alterations detected in human tumors, though they are rather less frequent in lymphomas. However, acquisition of the TP53 mutation was demonstrated to be one of the characteristic markers in mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) and prognostic value of the TP53 status has been recognized for these diseases. We present the complex analysis of the TP53 aberrations in 57 cases of MCL and 131 cases of DLBCL. The TP53 status was determined by functional analyses in yeast (FASAY) followed by cDNA and gDNA sequencing. The level of the p53 protein was assessed by immunoblotting and loss of the TP53-specific locus 17p13.3 was detected by FISH. Altogether, we detected 13 TP53 mutations among MCL cases (22.8%) and 29 TP53 mutations in 26 from 131 DLBCL cases (19.8%). The ratio of missense TP53 mutations was 76.9% in MCL and 82.8% in DLBCL. The frequency of TP53 locus deletion was rather low in both diseases, reaching 9.3% in MCL and 15.3% in DLBCL. The presence of TP53 mutation was associated with shorter overall survival (OS) and progression-free survival (PFS) in MCL. Among DLBCL cases, the TP53 mutations shortened both OS and PFS of patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and decreased both OS and PFS of patients with secondary DLBCL disease.
Assuntos
Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Prognóstico , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Prednisona/administração & dosagem , Rituximab/administração & dosagem , Vincristina/administração & dosagem , Leveduras/genéticaRESUMO
D-type cyclins are involved in cell cycle regulation and play an important role in the pathogenesis of lymphomas. Aberrant expression of cyclin D1 is associated with mantle cell lymphoma (MCL) and serves as a diagnostic marker of MCL. Analysis of cyclin D expression in tumor tissues of patients with diffuse large B-cell lymphoma (DLBCL) which comprises a heterogeneous group of tumors may contribute to their stratification. We analyzed expression of cyclin D1, D2, and D3 mRNAs in 30 MCL and 104 DLBCL patients using qRT-PCR and addressed their significance for disease outcome. We confirmed a high level of cyclin D1 mRNA in 29 MCL cases (97%). One case (3%) was identified as positive for cyclin D2. Expression of cyclin D1 was limited to MCL and did not occur in DLBCL. Overexpression of cyclin D2, which is rare in MCL, occurred more frequently in DLBCL (11 cases, 10.6%). We showed that high expression of cyclin D2 in DLBCL cases de novo decreased the overall survival rate (P=0.016) and progression-free survival (P=0.009). The expression pattern of cyclin D3 was similar in both types of studied lymphomas and it did not affect the disease outcome.
Assuntos
Biomarcadores Tumorais/metabolismo , Ciclina D/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma de Célula do Manto/metabolismo , Idoso , Biomarcadores Tumorais/genética , Ciclina D/genética , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-IdadeRESUMO
Xenograft models represent a promising tool to study the pathogenesis of hematological malignancies. To establish a reliable and appropriate in vivo model of aggressive human B-cell leukemia and lymphoma we xenotransplanted four p53-mutated cell lines and one ATM-mutated cell line into immunodeficient NOD/SCID IL2Rγ-null mice. The cell lines MEC-1, SU-DHL-4, JEKO-1, REC-1, and GRANTA-519 were transplanted intraperitoneally or subcutaneously and the engraftment was investigated using immunohistochemistry and flow cytometry. We found significant differences in engraftment efficiency. MEC-1, JEKO-1 and GRANTA-519 cell lines engrafted most efficiently, while SU-DHL-4 cells did not engraft at all. MEC-1 and GRANTA-519 massively infiltrated organs and the whole intraperitoneal cavity showing very aggressive growth. In addition, GRANTA-519 cells massively migrated to the bone marrow regardless of the transplantation route. The MEC-1 and GRANTA-519 cells can be especially recommended for in vivo study of p53-mutated chronic lymphocytic leukemia and ATM-mutated mantle cell lymphoma, respectively.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Subunidade gama Comum de Receptores de Interleucina/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Mutação , Proteína Supressora de Tumor p53/genética , Animais , Biomarcadores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Xenoenxertos , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Transplante HeterólogoRESUMO
The clinical course and therapy of mantle cell lymphoma (MCL) are heterogeneous and often unsatisfactory. Prognostic factors are needed to stratify the patients. Microvessel density (MVD) has prognostic significance in some malignancies. There is little information about the vasculature of MCL, although some antiangiogenic drugs are in use. We studied MVD using systematic uniform random sampling and unbiased counting frames in immunohistochemical reactions with anti-CD34 antibody in pre-therapeutic extramedullary MCL samples of 177 patients. We analyzed the relationship of MVD to overall survival (OS) and progression-free survival (PFS), as well as to proliferative activity (Ki-67), mantle cell lymphoma prognostic index (MIPI), morphological variant, pattern of growth, and localization. MVD varied widely: range 54.6-503.6 vessels/mm(2), median 158.2 vessels/mm(2). Higher MVD was associated with bone marrow infiltration at the time of diagnosis (P = 0.001). High MVD was associated with significantly worse OS (P = 0.04) only in patients treated with non-intensive (conventional) therapy. MVD correlated positively with MIPI scores but not with the proliferation, morphological variant, growth pattern, or localization. Univariate analysis identified a prognostic influence of morphological variant, MIPI, and proliferative activity on OS and PFS and a prognostic influence of bone marrow infiltration at the time of diagnosis on PFS. Multivariate analysis showed prognostic influence of MIPI and proliferative activity on OS and PFS only. In conclusion, this is the first clinicopathological study of MVD of MCL with long-term follow-up showing negative prognostic trends of high MVD in MCL and positive correlation of MVD and MIPI.
Assuntos
Linfoma de Célula do Manto/patologia , Antígenos CD34/análise , Biomarcadores Tumorais/análise , Proliferação de Células , Terapia Combinada , Intervalo Livre de Doença , Humanos , Antígeno Ki-67/análise , Linfoma de Célula do Manto/terapia , Microvasos/patologia , Microvasos/fisiologia , Prognóstico , Estudos RetrospectivosRESUMO
Although a prognostic model (MIPI, Mantle Cell Lymphoma International Prognostic Index) for patients with mantle cell lymphoma (MCL) has been established, its clinical significance for daily practice in the rituximab era remains controversial. Data of 235 unselected patients with MCL from the Czech Lymphoma Project Database were analyzed. MIPI, simplified MIPI (s-MIPI) and Ki-67 proliferation index were assessed for all patients and for a subgroup of 155 rituximab-treated (RT) patients. MIPI divided all patients into subgroups of low-risk (22%), intermediate-risk (29%) and high-risk (49%), with median overall survival 105.8 vs. 54.1 vs. 24.6 months, respectively (p < 0.001). s-MIPI revealed similar results. The validity of both indexes was confirmed in RT patients. We confirmed the Ki-67 index to be a powerful single prognostic factor for overall survival (64.4 vs. 20.1 months, p < 0.001) for all patients and for the RT subset. Our results confirm the clinical relevance of MIPI, s-MIPI and Ki-67 for risk stratification in MCL also in the rituximab era.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno Ki-67/metabolismo , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Biomarcadores/metabolismo , República Tcheca , Bases de Dados Factuais , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imuno-Histoquímica , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Rituximab , Transplante Autólogo , Resultado do TratamentoRESUMO
In rare disorders, there are often no standard therapy recommendations. Patients with refractory disease may require novel experimental approaches. Applied as second- up to fourth-line treatment, lenalidomide (10-25 mg perorally on days 1-21 in a 28-day cycle) was used in our cohort of four adult patients with aggressive, multisystem and relapsing diseases. Complete and long-lasting remissions (more than 1 year, no maintenance therapy) were achieved in patients with Langerhans cell histiocytosis (11 cycles, combination with dexamethasone and etoposide, consolidated by allogeneic blood stem cell transplant) and plasma-cell Castleman disease (15 cycles, monotherapy). Mixed response with complete disappearance of brain infiltrates was reached in Erdheim-Chester disease (6 cycles, monotherapy) and gastrointestinal bleeding was well controlled in multiple angiomatosis (9 cycles, combination with thalidomide). For disease activity evaluation each patient underwent fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography scan imaging, which was complemented by clinical and laboratory investigations.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Ensaios de Uso Compassivo , Histiocitose de Células de Langerhans/tratamento farmacológico , Doenças Raras , Terapia de Salvação/métodos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hiperplasia do Linfonodo Gigante/patologia , Intervalo Livre de Doença , Doença de Erdheim-Chester/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Histiocitose de Células de Langerhans/patologia , Humanos , Lenalidomida , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Doenças Raras/tratamento farmacológico , Estudos Retrospectivos , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Tomografia Computadorizada por Raios X , Transplante Autólogo , Transplante Homólogo , Resultado do TratamentoRESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoma in adults. There are specific alterations that appear repeatedly in DLBCL cases and play a role in lymphomagenesis or progression of the disease. Some aberrations were used as prognostic markers in the pre-rituximab era. Addition of rituximab to the classical anthracycline-based chemotherapy significantly increased the survival rate in DLBCL. Only few prognostic factors have been re-evaluated for patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). We performed complex analysis of the p53 tumor suppressor in collection of 75 DLBCL cases. Fifty-four patients were de novo cases, twenty-one cases developed into DLBCL by transformation from less aggressive disease. We determined functional status by analysis of separated alleles in yeast (FASAY) and analyzed the p53 mutations by cDNA sequencing. We assessed the level of the p53 protein by immunoblot analysis. We used FISH to analyze loss of the p53 and ATM (ataxia telangiectasia mutated) gene deletions. We detected 16 p53 mutations (21.3%) including the mutation activating non-sense-mediated RNA decay pathway. Deletion of the p53 allele was more common in cases with p53 mutation. Mutations and/or deletions of p53 had statistically significant negative impact on progression-free survival and tended to decrease also overall survival in 46 de novo DLBCL patients treated with R-CHOP. p53 aberrations are negative predictors for survival of DLBCL patients treated with R-CHOP.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Prednisona/uso terapêutico , Proteína Supressora de Tumor p53/genética , Vincristina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Sequência de Bases , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 17/genética , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica , Loci Gênicos , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prednisona/administração & dosagem , Prognóstico , Rituximab , Resultado do Tratamento , Proteína Supressora de Tumor p53/metabolismo , Vincristina/administração & dosagem , Adulto JovemRESUMO
Mantle cell lymphoma (MCL) is typified by translocation t(11;14)(q13;q32) causing upregulation of cyclin D1 and deregulation of cell cycle. The cyclin D1 activation plays a critical role in MCL pathogenesis but additional oncogenic events, such as aberrations of the ARF/MDM2/p53 pathway are also necessary for progression of the disease. We analyzed the p53 tumor suppressor in tumor tissue of 33 patients with MCL. The p53 status was determined by functional analyses in yeast (FASAY) and by cDNA sequencing. The level of the p53 protein was assessed by immunohistochemistry and immunoblotting. Loss of the p53-specific locus 17p13.3 was detected by FISH. Mutations in the p53 gene were detected in nine samples and they included eight missense mutations and one short deletion causing frame shift and premature stop codon formation in position 169. This mutation was associated with mRNA decay as revealed by sequencing of the p53 gDNA. All eight missense mutations were manifested by accumulation of the p53 protein in nuclei of tumor cells and three of them exhibited loss of the p53-specific locus 17p13.3. The p53 mutations were shown to be a negative prognostic marker in MCL.
Assuntos
Regulação Neoplásica da Expressão Gênica , Genes p53 , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Ciclina D1/biossíntese , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Translocação GenéticaAssuntos
Linfoma de Célula do Manto/etiologia , Transplante de Células-Tronco/efeitos adversos , Translocação Genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Evolução Fatal , Feminino , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/tratamento farmacológico , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Transplante Homólogo , Vincristina/uso terapêuticoRESUMO
The Hypertext Atlas of Dermatopathology, the Atlas of Fetal and Neonatal Pathology and Hypertext Atlas of Pathology (this one in Czech only) are available at http://www.muni.cz/atlases. These atlases offer many clinical, macroscopic and microscopic images, together with short introductory texts. Most of the images are annotated and arrows pointing to the important parts of the image can be activated.The Virtual Microscope interface is used for the access to the histological images obtained in high resolution using automated microscope and image stitching, possibly in more focusing planes. Parts of the image prepared in advance are downloaded on demand to save the memory of the user's computer. The virtual microscope is programmed in JavaScript only, works in Firefox/Mozilla and MSIE browsers without need to install any additional software.