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Patients with relapsed or refractory lymphoma have limited treatment options, requiring newer regimens. In this Phase 1/2 study (NCT03769181), we assessed the safety, efficacy, and pharmacokinetics of isatuximab (Isa, anti-CD38 antibody) in combination with cemiplimab (Cemi, anti-programmed death-1 [PD-1] receptor antibody; Isa + Cemi) in patients with classic Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma (PTCL). In Phase 1, we characterized the safety and tolerability of Isa + Cemi with planned dose de-escalation to determine the recommended Phase 2 dose (RP2D). Six patients in each cohort were treated with a starting dose of Isa + Cemi to determine the RP2D. In Phase 2, the primary endpoints were complete response in Cohort A1 (cHL anti-PD-1/programmed death-ligand 1 [PD-L1] naïve), and objective response rate in Cohorts A2 (cHL anti-PD-1/PD-L1 progressors), B (DLBCL), and C (PTCL). An interim analysis was performed when the first 18 (Cohort A1), 12 (Cohort A2), 17 (Cohort B), and 11 (Cohort C) patients in Phase 2 had been treated and followed up for 24 weeks. Isa + Cemi demonstrated a manageable safety profile with no new safety signals. No dose-limiting toxicities were observed at the starting dose; thus, the starting dose of each drug was confirmed as the RP2D. Based on the Lugano 2014 criteria, 55.6% (Cohort A1), 33.3% (Cohort A2), 5.9% (Cohort B), and 9.1% (Cohort C) of patients achieved a complete or partial response. Pharmacokinetic analyses suggested no effect of Cemi on Isa exposure. Modest clinical efficacy was observed in patients with cHL regardless of prior anti-PD-1/PD-L1 exposure. In DLBCL or PTCL cohorts, interim efficacy analysis results did not meet prespecified criteria to continue enrollment in Phase 2 Stage 2. Isa + Cemi did not have a synergistic effect in these patient populations.
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Doença de Hodgkin , Linfoma Difuso de Grandes Células B , Linfoma de Células T Periférico , Humanos , Antígeno B7-H1 , Anticorpos Monoclonais Humanizados/efeitos adversos , Doença de Hodgkin/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológicoRESUMO
BACKGROUND: Most patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) will relapse if treatment is withdrawn, but various trials have recently demonstrated that a significant proportion of patients who achieved a stable and deep molecular response (DMR) can stop therapy without relapsing. However, most information on treatment cessation was obtained from clinical trials with strict recruiting criteria. METHODS: We evaluated the outcome of 25 patients with CML that discontinued TKI therapy in our institute in real-world clinical practice. RESULTS: Of the 25 patients, 76% discontinued therapy in sustained deep molecular response (SDMR) and 24% were in unsustained DMR (UDMR). Discontinuation of therapy due to adverse effects was observed in 5 and 50% of the patients in the SDMR and UDMR groups, respectively. After TKI discontinuation, patients were followed for a median of 24 months. At the time of this analysis, 56% patients had a molecular relapse after a median of 4 months. SDMR and longer treatment duration were associated with lower probability of molecular relapse: 25% in SDMR patients with TKI treatment > 96 months and 85% in UDMR patients with TKI treatment ≤96 months. All relapsed patients promptly resumed TKI therapy and regained at least major molecular response (MMR). CONCLUSIONS: Our results suggest that TKI discontinuation is safe outside clinical trials and particularly effective in CML patients who are in SDMR with longer TKI treatment duration.
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Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Suspensão de Tratamento/tendências , Adolescente , Adulto , Idoso , Análise Citogenética/tendências , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Gastric mucosa-associated lymphoid tissue non-Hodgkin lymphoma (gMALT NHL) is the second most common gastrointestinal lymphoma (50% of all gastric lymphomas), being closely associated with Helicobacter pylori infection, justifying that antibiotic therapy is effective in over 75% of all cases. This is a retrospective study analyzing all adult gMALT NHL cases diagnosed and treated in a single center for 8 years, focusing on demographic features, treatment outcomes, and survival analysis. Sixty patients with a median age of 61 years (53.3% female gender) were analyzed. Most of the cases had localized disease (66.7% were Lugano stage I) and had low IPI scores (median: 1). There was a high prevalence of Helicobacter pylori infection (68.3%). Nearly 97% of the cases received treatment for the disease, a median of one line; 55% of the patients treated endured complete response after first-line therapy (mostly antibiotics). Median overall survival time and median progression-free survival time were not reached. The mean follow-up time was 81.8 months (95% CI: [73.3-90.3]). Thirty-six patients (60%) achieved a 3-year follow-up time; the mortality rate was 15% at the end of the study. Age superior to 65 years and transformation into DLBCL were statistically significant negative prognostic markers for survival in this study (p = 0.006 and p = 0.033, respectively). Our study confirms that gMALT NHL is an indolent disease with long-term survival. Many patients, however, are exposed to several treatment lines along their disease course.
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INTRODUCTION: Diffuse large B cell Lymphoma (DLBCL) is a potentially curative lymphoma with increasing incidence with ageing. Treatment of elderly DLBCL patients represents a particular challenge due to their comorbidities and performance status. METHODS: A search for original articles focused on the treatment of elderly DLBCL patients was performed in PubMed database and 633 were found and reviewed. Thirty-eight studies meeting our inclusion criteria were published since 2007. RESULTS: Thirteen studies were retrospective and 25 phase II/III clinical trials. Most of them investigated the efficacy of dose-adjusted R-CHOP regimen. Alternative therapeutic drugs together with geriatric assessment were also evaluated. For fit patients aged 80 and over, the strongest evidence favours R-miniCHOP regimen. CONCLUSION: A dose-adjusted R-CHOP may be the recommended treatment in elderly DLBCL patients. New tools such as the Comprehensive Geriatric Assessment provide useful guidance for treatment choice, based on comorbidities and frailty index of this group.
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Linfoma Difuso de Grandes Células B , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Comorbidade , Ciclofosfamida , Doxorrubicina , Avaliação Geriátrica , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/epidemiologia , Prednisona , Estudos Retrospectivos , Rituximab/uso terapêutico , Resultado do Tratamento , VincristinaRESUMO
Gastric diffuse large B cell lymphoma (DLBCL) represents the majority of all gastric lymphomas. We report a series of gastric DLBCL diagnosed and treated in a single center, between 2010 and 2018 (included). We retrospectively analyzed the population demographic features, treatment outcomes and survival. One-hundred-and-one patients were studied, 50.5% males and median age of 64 years [23-94]. Lugano staging was I in 16.8%, II1 in 20.8%, II2 in 10.9%, IIE in 13.9% and IV in 34.7% of cases. Twenty percent had Helicobacter pylori infection. R-CHOP-like therapy was used as first line in 96.9% of the patients. A complete response was achieved in 80% after first line therapy. At 3-years of follow-up (FU), 54% were in complete remission. The mean FU time was 73.6 months. Median overall survival and median progression free survival were not reached. We identified seven factors with negative impact in survival: age above 65 years-old (p < 0.01), ECOG 2-3 (p < 0.01), B symptoms (p = 0.001), bulky disease (p = 0.003), IPI 3-4 (p = 0.001), more than 3 treatment lines (p < 0.01), absence of response to first line treatment (p < 0.01). This study demonstrates that gastric DLBCL is a potentially curable disease with R-CHOP-like therapy, entailing long term survival and comparing well with other published series.
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Human immunodeficiency virus (HIV) patients have an increased incidence of lymphomas, particularly when there is a significant immunosuppression. Most commonly, they are non-Hodgkin B cell type with a high or intermediate grade and have an extranodal presentation. We report the case of a 38-year-old man with HIV infection who presented with a 1-year history of a painless tumor on the back and lymphadenopathies. The diagnosis of B cell lymphoma follicle center cell type was established by skin biopsy. Staging included a bone marrow biopsy revealing infiltration by the lymphoma and a whole-body computed tomographic scan showing multiple cervical and axillary lymphadenopathies with necrotic center. Biopsy of an axillary lymph node revealed caseating epithelioid granulomas and Ziehl-Neelson staining was positive for acid-fast bacilli. The patient started therapy for tuberculosis and polychemotherapy for lymphoma with complete response. This report illustrates a case of simultaneous occurrence of tuberculosis and systemic follicular lymphoma presenting in skin in an HIV patient.
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Linfoma Relacionado a AIDS/patologia , Linfoma Folicular/patologia , Tuberculose Cutânea/patologia , Adulto , Antineoplásicos/uso terapêutico , Biópsia por Agulha , Diagnóstico Diferencial , Seguimentos , Humanos , Imuno-Histoquímica , Doenças Linfáticas/patologia , Linfoma Relacionado a AIDS/diagnóstico , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamento farmacológico , Masculino , Medição de Risco , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Tuberculose Cutânea/diagnóstico , Tuberculose Cutânea/tratamento farmacológicoRESUMO
Acute myeloid leukemia (AML) is a clonal hematological malignant condition and the implications of pretreatment risk criteria as predictive or prognostic factors are constantly under evaluation. With this study, the authors' intent was to characterize AML patients and to evaluate the clinical outcome associated with Southwestern Oncology Group (SWOG) coding pretreatment risk criteria/cytogenetic score. Between 2002 and 2010, 225 patients were diagnosed with AML at the Portuguese Institute of Oncology (Porto, Portugal). From this patient group, 128 patients aged <65 years were selected. The patients were treated using a combination of cytarabine and anthracycline, with the addition of cyclosporine when bone marrow dysplasia was observed. A median survival of 24 months was observed in this group. The patients were divided in subgroups according to the SWOG pretreatment risk criteria. We observed a statistically significant association of non-favorable SWOG coding with female gender [P=0.025; risk ratio (RR)=3.632, 95% confidence interval (CI): 1.113-11.852], indication for allogeneic bone marrow transplantation (P=0.023, RR=1.317, 95% CI: 1.184-1.465), complete response achievement (P=0.013, RR=1.385, 95% CI: 11.232-1.556) and relapse (P=0.048, RR=3.181, 95% CI: 10.966-10.478). Furthermore, SWOG pretreatment risk criteria also significantly affected global overall survival (OS; P=0.003) and OS at 5 years (P=0.001). A multivariate Cox regression analysis supported response to induction therapy (3-year OS: P=0.011, RR=0.385, 95% CI: 10.184-0.806; 5-year OS: P=0.012, RR=0.388, 95% CI: 10.597-1.994), consolidation (3-year OS: P=0.005, RR=0.328, 95% CI: 0.150-0.720; 5-year OS: P=0.002, RR=0.308, 95% CI: 0.144-0.657) and the diagnosis of therapy-related aml (3-year OS: P=0.016, RR=2.756, 95% CI: 0.486-1.281; 5-year OS: P=0.031, RR=2.369, 95% CI: 1.081-5.189) as prognostic factors, but this was not confirmed for SWOG pretreatment risk criteria. Therefore, we concluded that the reproducibility of the application of the SWOG pretreatment risk criteria may not be available as a prognostic factor in every acute leukemia population. However, its application as a predictive factor of response has been confirmed in our population.
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BACKGROUND: GP2013 is a rituximab biosimilar developed to stringent development guidelines, including non-clinical and preclinical investigations and clinical trials in rheumatoid arthritis and follicular lymphoma. We aimed to compare the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of GP2013 plus cyclophosphamide, vincristine, and prednisone (GP2013-CVP) with rituximab-CVP (R-CVP) in patients with follicular lymphoma. METHODS: In this phase 3, multinational, double-blind, randomised, controlled trial, adults (aged 18 years or older) with previously untreated, advanced stage (Ann Arbor stage III or IV) follicular lymphoma of WHO histological grades 1, 2, or 3a were randomly assigned (1:1) using interactive response technology to eight cycles of GP2013-CVP or R-CVP (combination phase), followed by monotherapy maintenance in responders for a 2-year period. Randomisation was stratified by Follicular Lymphoma International Prognostic Index risk group and geographic region. The primary endpoint was comparability in overall response, with equivalence concluded if the entire 95% CI was within a margin of -12% to 12%. The primary endpoint was analysed using the per-protocol set, which included all patients who received at least one (partial or complete) dose of investigational treatment and who did not have any major protocol deviations. The trial is registered with ClinicalTrials.gov, number NCT01419665, and is ongoing. FINDINGS: Between Dec 1, 2011, and Jan 15, 2015, 858 patients were screened for eligibility. 314 patients were randomly assigned to GP2013, of whom 312 were given GP2013, and 315 were assigned to reference rituximab. Median follow-up was 11·6 months (IQR 5·8-18·2) for the primary analysis. The primary endpoint, equivalence of overall response, was met (271 [87%] of 311 patients with GP2013 and 274 [88%] of 313 patients with reference rituximab achieved an overall response; difference -0·40% [95% CI -5·94 to 5·14]). Occurrence of adverse events and serious adverse events was similar between the treatment groups (289 [93%] of 312 patients in the GP2013-CVP group had an adverse event and 71 [23%] of 312 patients had a serious adverse event; 288 [91%] of 315 patients in the R-CVP group had an adverse event and 63 [20%] had a serious adverse event). The most common adverse event was neutropenia (80 [26%] of 312 patients in the GP2013-CVP group and 93 [30%] of 315 patients in the R-CVP group in the combination phase and 23 [10%] of 231 patients in the GP2013-CVP group and 13 [6%] of 231 patients in the R-CVP group in the maintenance phase). The most common grade 3 or 4 adverse event during the combination and maintenance phase was neutropenia (55 [18%] of 312 patients in the GP2013-CVP group and 65 [21%] of 315 patients in the R-CVP group in the combination phase and 17 [7%] of 231 patients in the GP2013-CVP group and nine [4%] of 231 patients in the R-CVP group in the maintenance phase). The occurrence of anti-drug antibodies was similar in the treatment groups (five [2%] of 268 patients in the GP2013-CVP; three [1%] in the R-CVP group). INTERPRETATION: Our results show that GP2013 represents a viable rituximab biosimilar candidate for patients with previously untreated advanced follicular lymphoma. The introduction of biosimilars provides additional therapeutic options with potential to increase access to effective and life-saving biological therapies such as rituximab. FUNDING: Hexal.
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Medicamentos Biossimilares/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Rituximab/uso terapêutico , Adolescente , Adulto , Idoso , Medicamentos Biossimilares/efeitos adversos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Referência , Rituximab/efeitos adversos , Segurança , Adulto JovemRESUMO
Therapy-related acute myeloid leukemia (t-AML) is a rare and almost always fatal late side effect of antineoplastic treatment involving chemotherapy, radiotherapy or the two combined. The present retrospective study intended to characterize t-AML patients that were diagnosed and treated in a single referral to an oncological institution in North Portugal. Over the past 10 years, 231 cases of AML were diagnosed and treated at the Portuguese Institute of Oncology of Porto, of which 38 t-AML cases were identified. Data regarding the patient demographics, primary diagnosis and treatment, age at onset of therapy-related myeloid neoplasm, latency time of the neoplasm, cytogenetic characteristics, AML therapy and outcome were collected from medical records. A previous diagnosis with solid tumors was present in 28 patients, and 10 patients possessed a history of hematological conditions, all a lymphoproliferative disorder. Breast cancer was the most frequent solid tumor identified (39.5% of all solid tumors diagnosed). The mean latency time was 3 years. In the present study, t-AML patients were older (P<0.001) and more frequently carried cytogenetic abnormalities (P=0.009) compared with de novo AML patients. The overall survival time was observed to be significantly poorer among individuals with t-AML (P<0.001). However, in younger patients (age, <50 years) there was no difference between the overall survival time of patients with t-AML and those with de novo AML (P=0.983). Additionally, patients with promyelocytic leukemia possess a good prognosis, even when AML occurs as a secondary event (P=0.98). To the best of our knowledge, the present study is the first to evaluate t-AML in Portugal and the results are consistent with the data published previously in other populations. The present study concludes that although t-AML demonstrates a poor prognosis, this is not observed among younger patients or promyelocytic leukemia patients.
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PURPOSE: Investigation of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) using molecular markers has proven superior to other standard criteria (age, sex, and WBC) in distinguishing patients at high, intermediate, and low risk of relapse. The aim of our study was to determine whether MRD investigation is valuable in predicting outcome in Philadelphia-negative adult patients with ALL. PATIENTS AND METHODS: MRD was assessed in 85 adult patients with B-lineage ALL by semiquantitative immunoglobulin H gene analysis on bone marrow samples collected during four time bands in the first 24 months of treatment. Fifty patients received chemotherapy only and 35 patients received allogeneic (n = 19) or autologous (n = 16) bone marrow transplantation (BMT) in first clinical remission. The relationship between MRD status and clinical outcome was investigated and compared with age, sex, immunophenotype, and presenting WBC count. RESULTS: Fisher's exact test established a statistically significant concordance between MRD results and clinical outcome at all times. Disease-free survival (DFS) rates for MRD-positive and -negative patients and log-rank testing established that MRD positivity was associated with increased relapse rates at all times (P <.05) but was most significant at 3 to 5 months after induction and beyond. MRD status after allogeneic BMT rather than before was found to be an important predictor of outcome in 19 adult patients with ALL tested. In patients receiving autologous BMT (n = 16), the MRD status before BMT was more significant (P =.005). CONCLUSION: The association of MRD test results and DFS was independent of and greater than other standard predictors of outcome and is therefore important in determining treatment for individual patients.
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Biomarcadores Tumorais/análise , DNA de Neoplasias/análise , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adulto , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Intervalo Livre de Doença , Feminino , Humanos , Imunoglobulinas/análise , Imunofenotipagem , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Prognóstico , Recidiva , Fatores de Risco , Fatores Sexuais , Resultado do TratamentoRESUMO
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm characterized by sustained neutrophilia and the absence of the Philadelphia chromosome or the BCR-ABL1 fusion gene. The present study reports the case of a 59-year-old Caucasian female that was referred to The Francisco Gentil Portuguese Institute of Oncology (Porto, Portugal) with constitutional symptoms (mainly asthenia), marked leukocytosis (51.33×109/l with 90% neutrophils), macrocytic anemia and splenomegaly. Bone marrow aspiration and biopsy revealed hypercellular marrow with clear predominance of segmented neutrophils. The karyotype was normal and the BCR-ABL1 fusion gene was not detected. After excluding a leukemoid reaction, a diagnosis of CNL was established. The clinical follow-up was complicated by hemorrhagic brain lesions and relapsing episodes of erythematous, well-demarcated and painful subcutaneous nodular lesions, consistent with Sweet's syndrome (SS). Multiple treatment strategies were administered, including use of hydroxyurea, imatinib and intensive chemotherapy. Nevertheless, progression was documented and the patient succumbed at 28 months post-diagnosis. The clinical course of CNL varies, and can be complicated by cerebral hemorrhage, blastic transformation or infection. Dermatological manifestations such as SS have seldom been reported in association. No evidence-based treatment currently exists and the majority of our knowledge is based on results from case reports and small series.
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INTRODUCTION: The objective of the study was to reduce, by a bundle of interventions, the global bloodstream infections and catheter-related bloodstream infections rates in neutropenic hematology patients with a long-term central venous catheter. MATERIAL AND METHODS: This was a non-randomized prospective study. It was conducted in a 20-bed hematology oncology unit (Portuguese Institute of Oncology, Porto, Portugal) between 1st of August 2010 and 31st of January 2012. In this period we introduced a bundle of interventions (study group) and compared the results with the six months prior to implementation (control group). The interventions consisted in the use of a neutral pressure mechanical valve connector instead of a positive pressure mechanical valve connector, a more frequent change of this connector and a more efficient clean solution. One hundred and sixteen hematology patients with a long-term central venous catheter at time superior of 72 h, with 8 867 central venous catheter days [6 756 central venous catheter days in the study group and 2 111 central venous catheter days in the control group] were included in the study. RESULTS: A significant reduction in bloodstream infections rates and catheter-related bloodstream infections rates was achieved. Bloodstream infections rates: [32.69 (control group) vs. 9.43 (study group)], incidence reduction 71% [relative risk 0.2886, CI 95% (0.1793 - 0.4647), p < 0.001] and catheter-related bloodstream infections rates: [17.53 (control group) vs. 4.73 (study group)], incidence reduction 71% [relative risk 0.2936, CI 95% (0.1793 - 0.5615), p < 0.014]. No significant difference (p > 0.05) was found in the neutrophil count at the time of blood culture samples between groups: 69% (< 500 neutrophils/mm3) [71% (study group) vs. 68% (control group)]. CONCLUSIONS: The introduction of this bundle of interventions based on the variables of patient, product and practice, supported by the Healthcare and Technology Synergy framework, quickly resulted in a significant reduction of bloodstream infections and catheter-related bloodstream infections rates.
Introdução: O objetivo deste estudo foi reduzir através de um pacote de medidas as infeções sistémicas e as taxas de infeções com origem no cateter venoso central nos doentes hematológicos em neutropenia com cateter venoso central de longa duração. Material e Métodos: Estudo prospetivo não randomizado realizado na unidade onco-hematológica do Instituto Português de Oncologia do Porto no período compreendido entre 1 de agosto de 2010 até 31 de janeiro de 2012. Durante este período foi introduzido um pacote de medidas (grupo estudo) e comparados os resultados nos 6 meses anteriores à sua implementação (grupo de controlo). As medidas consistiram na utilização de conectores de pressão neutra em detrimento dos conectores de pressão positiva, na sua troca mais frequente e numa solução anti-séptica mais eficaz. Foram incluídos neste estudo 116 doentes hematológicos com cateter venoso central de longa duração inserido por um período superior a 72 h. Foram contabilizados 8 867 dias de cateter (6 756 dias de cateter venoso central no grupo estudo e 2 111 dias de cateter venoso central no grupo de controlo). Resultados: Obteve-se uma redução significativa nas taxas de infeções sistémicas e infeções com origem no cateter venoso central. As taxas de infeções sistémicas: [32,69 (grupo de controlo) vs. 9,43 (grupo estudo)], com uma redução de incidência de 71% [risco relativo 0,2886, CI 95% (0,1793 - 0,4647), p < 0,001] e taxas de infeções com origem no cateter venoso central: [17,53 (grupo de controlo) vs. 4,73 (grupo estudo)], com redução de incidência de 71% [risco relativo 0,2936, CI 95% (0,1793 - 0,5615), p < 0,014]. Não foi encontrada diferença significativa (p > 0,05) na contagem de neutrófilos à data da colheita das amostras de hemoculturas entre ambos os grupos: 69% (< 500 neutrófilos/mm3) [71% (grupo estudo) vs. 68% (grupo de controlo)]. Conclusões: A introdução deste pacote de medidas baseado nas variáveis do paciente, produto e prática, suportado pela estrutura Healthcare and Technology Synergy, resultou numa redução significativa das taxas de infeções sistémicas e infeções com origem no cateter venoso central.
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Bacteriemia/prevenção & controle , Infecções Relacionadas a Cateter/prevenção & controle , Cateterismo Venoso Central/efeitos adversos , Cateteres Venosos Centrais/efeitos adversos , Humanos , Neutropenia , Portugal , Pressão , Estudos ProspectivosRESUMO
We report the case of a boy with hereditary spherocytosis who presented with mild microcytic hypochromic anemia and recurrent leg ulcers that had been present since childhood. Chronic natural killer (NK) cell and B-cell lymphocytosis was detected 1 year after therapeutic splenectomy during investigation of recurrent episodes of neutropenia and persistent lymphocytosis. NK cells proved to be abnormal at immunophenotyping studies, and B-cells were polyclonal and displayed a normal immunophenotype. Genotypic analysis of T-cell receptor (TCR)-beta and TCR-gamma genes showed a germ-line pattern. The clinical course of this patient was characterized by multiple pulmonary infections and amygdalitis. We discuss the potential roles of persistent immune stimulation due to chronic hemolysis and severe leg ulcers and of splenectomy in the origin of NK cell lymphocytosis and the relationship between NK cells and recurrent infections, relapsing neutropenia, and polyclonal B-cell response.
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Células Matadoras Naturais/patologia , Linfocitose/etiologia , Esplenectomia/efeitos adversos , Linfócitos B/citologia , Criança , Humanos , Sistema Imunitário/patologia , Infecções/complicações , Linfocitose/patologia , Masculino , Neutropenia/complicações , Recidiva , Esferocitose Hereditária/complicações , Esferocitose Hereditária/terapiaRESUMO
Chromosomal rearrangements affecting the MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemia. In this study, conventional cytogenetic, fluorescence in situ hybridization, and molecular genetic studies were used to characterize the type and frequency of MLL rearrangements in a consecutive series of 45 Portuguese patients with MLL-related leukemia treated in a single institution between 1998 and 2011. In the group of patients with acute lymphoblastic leukemia and an identified MLL fusion partner, 47% showed the presence of an MLL-AFF1 fusion, as a result of a t(4;11). In the remaining cases, a MLL-MLLT3 (27%), a MLL-MLLT1 (20%), or MLL-MLLT4 (7%) rearrangement was found. The most frequent rearrangement found in patients with acute myeloid leukemia was the MLL-MLLT3 fusion (42%), followed by MLL-MLLT10 (23%), MLL-MLLT1 (8%), MLL-ELL (8%), MLL-MLLT4 (4%), and MLL-MLLT11 (4%). In three patients, fusions involving MLL and a septin family gene (SEPT2, SEPT6, and SEPT9), were identified. The most frequently identified chromosomal rearrangements were reciprocal translocations, but insertions and deletions, some cryptic, were also observed. In our series, patients with MLL rearrangements were shown to have a poor prognosis, regardless of leukemia subtype. Interestingly, children with 1 year or less showed a statistically significant better overall survival when compared with both older children and adults. The use of a combined strategy in the initial genetic evaluation of acute leukemia patients allowed us to characterize the pattern of MLL rearrangements in our institution, including our previous discovery of two novel MLL fusion partners, the SEPT2 and CT45A2 genes, and a very rare MLL-MLLT4 fusion variant.
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Rearranjo Gênico , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Lactente , Cinesinas/genética , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Miosinas/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Prognóstico , Fatores de Transcrição/genética , Fatores de Elongação da Transcrição , Adulto JovemRESUMO
Minimal residual disease (MRD) was investigated in 52 children with acute lymphoblastic leukaemia (ALL), using antigen receptor gene rearrangements and reverse transcription polymerase chain reaction for fusion transcripts as molecular targets. Patients [treated according to the Medical Research Council United Kingdom ALL (MRC UKALL) XI protocol or Total XI and XIII protocols] were monitored for a median period of 45 months (range, 9-110 months). Among 17 patients who relapsed, MRD persisted for longer (66.7%, 47.1%, 53.8% and 41.7% at 0-2, 3-5, 6-9, 10-24 months respectively) than patients who remained in continuous clinical and immunological remission (n = 35) (27.3%, 11.1%, 4.3%, 8.0%). Association between MRD tests and outcome was assessed and found to be significant at all time-points. The difference in survival for MRD-positive and MRD-negative patients (using the log-rank test) was statistically significant at all time intervals, as was risk of relapse for MRD-positive patients (1.89, 2.20, 2.65 and 2.16) and MRD-negative patients (0.72, 0.82, 0.65 and 0.70). Sixteen of the 52 patients had an oligoclonal pattern at presentation but oligoclonality did not have an impact on outcome. Cox regression analysis revealed that MRD assessment is an independent and prognostically significant factor during treatment and should be used for patients' stratification in future studies.